benign endometrium: dysfunctional bleeding, breakdown

BENIGN ENDOMETRIUM: DYSFUNCTIONAL BLEEDING,
BREAKDOWN, AND METAPLASIA
Michael T. Mazur, M.D.
ClearPath Diagnostics
600 E. Genesee St.
Syracuse, NY 13066
mmazur@clearpathdiagnostics.com
Abnormal uterine bleeding (AUB) is a common sign of a number of different uterine
disorders ranging from dysfunctional (nonorganic) abnormalities or complications of pregnancy
to organic lesions such as polyps, hyperplasia, or carcinoma.(1-7) In many cases, AUB leads to
endometrial biopsy or curettage that can present unique diagnostic challenges for pathologists.
There are a variety of terms are applied to AUB. Dysfunctional uterine bleeding (DUB) refers to
bleeding due to ovulatory dysfunction with no other uterine or systemic abnormality present.
Post-menopausal bleeding (PMB) describes uterine bleeding one year after the cessation of
menses. By definition, DUB excludes postmenopausal bleeding or bleeding due to the presence
of specific pathologic processes such as inflammation, polyps, hyperplasia, carcinoma,
exogenous hormone effects, and complications of pregnancy. The endometrial changes
associated with DUB are important to recognize, because they may be confused with more
serious lesions such as hyperplasia.
A frequent concern, especially in the perimenopausal and postmenopausal patient, is the
presence of hyperplasia or carcinoma of the endometrium. Overt hyperplasia or neoplasia often
is the least troublesome problem from a diagnostic point of view. A variety of other, benign
patterns are more commonly seen and present some of the greatest challenges in biopsy
interpretation since they are difficult to catalog. Artifacts, superimposed patterns of breakdown
and bleeding, ovulatory disorders, hormonal effects, and metaplasia all contribute to the
complexities of interpreting these cases.
1
DYSFUNCTIONAL UTERINE BLEEDING
Dysfunctional uterine bleeding is a clinical term that refers to bleeding due to
irregularities in ovarian function, so it is most common at the time of menopause. DUB is largely
a diagnosis of exclusion once other etiologies such as organic lesions, endometritis and systemic
bleeding disorders are ruled out.(8-12) Endometrial biopsy or curettage is usually done to
determine if endometrial changes are consistent with DUB and to exclude other causes of
bleeding, especially organic lesions in the perimenopausal woman. These biopsies are common
in many practices, usually showing benign changes that may be complicated by breakdown and
bleeding and by abnormal endometrial development that is neither hyperplastic nor neoplastic.
DUB-associated patterns have the stigma of lacking glamour of a more rare and
significant diagnosis such as atypical hyperplasia. Despite their somewhat banal nature, they can
be complicated to interpret and may require considerable study. The terminology applied to the
consequences of dysfunctional patterns also has not been the target of strict conventions of
nomenclature, probably allowing many different terms for groups of fundamentally similar
changes.
DUB can be due to anovulatory cycles or to disorders in follicle development during the
luteal phase. In most cases, DUB is due to anovulatory cycles, and some authors regard
anovulation as the only cause. Alternatively, however, a shortened or prolonged luteal phase
may also lead to abnormal bleeding, concepts known as “luteal phase defect” and “irregular
shedding.”
Anovulatory bleeding pattern (proliferative with glandular and stromal breakdown).
Most cases of DUB are due to anovulatory cycles, a sporadic but common occurrence, especially
in perimenarchal and perimenopausal women.(2) Anovulatory cycles are also a component of
polycystic ovarian disease or Stein-Leventhal syndrome with more persistent endocrine
imbalance in the reproductive years.
In the normal menstrual cycle a cohort of follicles is recruited and they begin to develop
and produce estradiol. A dominant follicle then ruptures following the LH surge at mid-cycle.
After the follicle ruptures, a corpus luteum develops, producing progesterone as well as estradiol.
2
In anovulatory cycles the follicles are recruited but there is no ovulation, usually due to disorders
at the hypothalamus/pituitary level or feedback signals. As a consequence, there is a surge of
estradiol without progesterone from a corpus luteum. The follicle or follicles can either involute
leading to estrogen withdrawal or persist leading to sustained estrogen stimulation of the
endometrium. In either event the endometrium proliferates without a normal luteal phase. With
estrogen withdrawal, breakdown occurs in a weakly proliferative background as the estrogen
stimulus wanes (estrogen withdrawal bleeding). With estrogen persistence, the endometrium
continues to proliferate with thrombi forming in superficial vessels leading to areas of
breakdown (estrogen breakthrough bleeding). In either case the breakdown often affects only a
portion of the endometrium.
The usual morphologic reflection of anovulatory cycles is a proliferative phase pattern,
often with fibrin thrombi in small vessels and breakdown and bleeding superimposed. If active
bleeding is not taking place at the time of biopsy, then the changes are simply those of
proliferative phase patterns. These common histologic findings are important to observe since
they provide useful information for the gynecologist. Tissue fragmentation and artifacts along
with the breakdown patterns often distort the tissue, but the anovulatory bleeding pattern usually
is recognizable.
Disordered proliferative phase. The disordered proliferative phase pattern usually is an
extension of anovulatory cycles due to persistent estrogen stimulation. In this situation the
endometrium is proliferative but shows focal gland irregularities including dilatation and
branching like that seen in hyperplasia. In contrast to hyperplasia, however, gland irregularities
are mild and focal in the disordered proliferative phase pattern.
The diagnosis of disordered proliferative phase pattern has become commonplace in
many practices. This term is often overused and misapplied, however. Changes such as
fragmentation, telescoping and even portions of basalis can be misclassified as disordered
proliferative phase patterns. In addition, the distinction between disordered proliferative patterns
and simple hyperplasia is blurred in some situations. To be clinically useful this diagnosis
should be reserved for those cases that truly show focal irregularities in proliferative gland
3
development. Besides anovulatory cycles, limited sampling of a polyp may yield a pattern of
disordered glands.
DUB and secretory changes. DUB may also develop when ovulation occurs but the
corpus luteum does not develop and persist for a normal duration over the last half of the
menstrual cycle. Disturbances in the rate and amount of progesterone produced by the granulosa
cells of the corpus luteum result in alterations in the pattern of secretory phase development.
These changes may be due to insufficient development or persistence of the corpus luteum
(luteal phase defect, LPD) or to abnormal persistence of a corpus luteum (irregular shedding).
(13-16)
Luteal phase defect and irregular shedding are less well-defined entities. These
conditions, if they occur, are sporadic and not amenable to detailed clinical-pathologic
correlations to clearly define the morphologic changes. There are no well-defined morphologic
changes that are diagnostic of disturbed corpus luteum function. There are clear situations,
however, where there is abnormal secretory phase maturation with or without superimposed nonmenstrual breakdown.
The term “irregular maturation” describes secretory endometrium that does not show a
normal and universal pattern of secretory development that allows clear histologic dating
according to established criteria. The endometrium can show marked variation in secretory
development from area to area with some glands demonstrating tortuosity and secretions while
other glands are underdeveloped, lacking these changes. It is not clear that these patterns truly
reflect an inadequate corpus luteum, but the descriptive diagnosis serves to indicate that
abnormal but benign secretory changes are present and clinical correlation is needed. When
bleeding is present in a secretory but non-menstrual background, a descriptive diagnosis of
“secretory bleeding pattern” with a brief comment serves to communicate the changes to the
clinician. Rarely irregular shedding may result in a mixed phase pattern due to abnormal
persistence of the corpus luteum. In this case portions of the endometrium are secretory and
others areas have proliferative features.
Recognition of abnormal secretory phase patterns is important. The best method to detect
these changes is to recognize when secretory endometrium does not show a consistent pattern of
4
normal “datable” changes. Usually, it is not possible to determine the etiology, and there are a
number of possible causes of abnormal secretory changes in addition to ovulatory dysfunction
(Table 1). Consequently, a descriptive diagnosis without assigning an underlying cause is the
best approach for the pathologist.
BREAKDOWN PATTERNS AND METAPLASIA
Glandular and stromal breakdown. When endometrium undergoes acute nonphysiologic (non-menstrual) breakdown and bleeding, glandular and stromal changes occur that
are almost unique to this tissue.(1) Fibrin thrombi form in small arteries and capillaries or in
dilated superficial venules resulting in apoptosis with nuclear debris at the base of glands and
within the stroma.(17-19) The devitalized tissue then demonstrates a characteristic pattern of
collapse as the stromal cells condense into tight clusters with scant cytoplasm and
hyperchromatic, closely apposed nuclei. As these clusters of stroma ("blue balls") separate from
underlying intact endometrium, they often retain a cap of epithelial cells, resulting in small round
to polypoid tissue fragments. The breakdown pattern is highly variable, ranging from limited
foci to diffuse changes with extensive fragmentation of the tissue. As bleeding continues and
becomes chronic the endometrium may show other features including hemosiderin deposition,
foam cells, and stromal hyalinization (Table 2).
Another change that reflects breakdown and bleeding is eosinophilic syncytial change
(ESC).(20-22) This alteration, also termed “papillary syncytial change,” occurs along the
surface epithelium, occasionally extending superficially into glands. Other features of active
bleeding such as stromal collapse are almost always present in close proximity or subjacent to
ESC. Previously this phenomenon was termed “papillary syncytial metaplasia,”(23) but it is
more degenerative than metaplastic. ESC shows no to minimal proliferative activity.(24)
ESC is characterized by aggregates of stratified eosinophilic cells, often forming small
papillary-like tufts lacking a connective tissue core. The syncytial aggregation of pink epithelial
cells over clusters on condensed stroma contributes to the pseudo-papillary arrangements. The
5
cells of ESC are generally oval, and their nuclei have a random, haphazard distribution. The
cytoplasm is pale to eosinophilic with occasional vacuoles. Cell borders are indistinct. Overall,
the nuclei are cytologically bland, but some cases of ESC show mild nuclear atypia manifested
by slight hyperchromasia, pleomorphism, and irregular nuclear outlines. ESC consistently has
associated cellular necrotic debris and often has a neutrophilic infiltrate, too. This abnormality
can be confused with metaplasia, atypia, or neoplasia. In contrast to metaplastic or neoplastic
lesions that largely involve glands, however, ESC is usually limited to surface epithelium.
Metaplasia.
Endometrial epithelium can show a variety of cytoplasmic changes
commonly termed “metaplasia.” These epithelial changes frequently occur in endometria that
contain hyperplasia or neoplasia, but they can occur in a variety of other benign conditions,
especially polyps. Many disorders previously classified as metaplasia are better termed "change"
since they are not true metaplastic transformations of the epithelium.(1)
There are five general types of cytoplasmic change seen in the endometrium.(25) These
are squamous, ciliated cell (tubal), eosinophilic, mucinous and secretory (clear cell) change.
Eosinophilic cell change often is cytologically related to tubal metaplasia but lacks cilia.
Association of eosinophilic cell change with mucinous metaplasia in some cases suggests a
relation between the two cell types with eosinophilic change representing a subtype of immature
mucinous metaplasia.(26) Tubal metaplasia usually shows immunoreactivity for p16 as well as
aberrant expression of some cell cycle proteins, suggesting it has potential to be a premalignant
lesion.(27) Progestin therapy or hyperplasia and well-differentiated adenocarcinoma can further
enhance various patterns of cytoplasmic change or metaplasia.(28;29) Eosinophilic syncytial
change, discussed above along with other features of breakdown and bleeding, is not a
metaplasia and is unrelated to the other forms of cytoplasmic transformation.
Like some changes in breakdown such as artifactual crowding and ESC, metaplastic
patterns complicate and confound the interpretation of specimens. Since metaplasia frequently
accompanies hyperplasia or well-differentiated carcinoma, separating benign metaplastic
changes from atypical changes is of paramount importance. One issue with metaplasia is that
these changes, except for secretory change and endocervical-type mucinous change, result in
cytoplasmic eosinophilia, a feature shared with gland cells in atypical hyperplasia and low grade
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adenocarcinoma as well as the unrelated phenomenon of ESC. The cytologic details of cells in
question are the key to making the critical distinction. Metaplastic change should show no
atypia. The cells may be pseudostratified in metaplasia, but orientation to the basement
membrane is maintained in contrast to atypical epithelium that shows loss of polarity in relation
to the underlying basement membrane. The nuclei of metaplasia lack atypia, a feature of
atypical hyperplasia (Table 3) and many well differentiated adenocarcinomas. Squamous change
presents a different challenge. Squamous change complicates gland patterns because the process
can result in crowding of the glands secondary to distention by nests of non-keratinizing
squamous cells. In this situation, the other histologic features including cellular atypia of the
glandular component and, in the case of carcinoma, confluent gland arrangements, determine the
correct diagnosis.
TERMINOLOGY
For abnormal endometrium that lacks a specific organic abnormality, selecting the best
diagnostic term can be as challenging as the interpretation of the specimen. The gynecologist
wishes to know the following:
1) Is there an organic lesion such as a complication of pregnancy, inflammation or a
polyp?
2) Is there evidence of active or old breakdown and bleeding?
3) Is there evidence to suggest dysfunctional bleeding?
4) Is there evidence of hyperplasia, atypia, or carcinoma?
When a biopsy is done for DUB, the report should address the presence or absence of
morphologic changes of breakdown and bleeding as well as any specific lesions. If the pattern is
that of proliferative endometrium with breakdown and if the clinical history is appropriate, the
changes can be accurately attributed to anovulatory cycles. A descriptive diagnosis such as
“proliferative endometrium with glandular and stromal breakdown” offers a clear morphologic
7
interpretation of the bleeding pattern that often is sufficient for clinical management. An
additional comment indicating that the change is compatible with anovulatory cycles helps to
clarify the diagnosis. If the changes show non-menstrual secretory endometrium with
breakdown but these are not diagnostic of a defined
eiomy phase abnormality, descriptive
terms such as “secretory bleeding pattern” communicates the observation of an abnormal yet
benign appearance while not assigning definite morphologic etiology. In general a comment
regarding the absence of other possible causes of bleeding such as hyperplasia, inflammation,
pregnancy, or polyps is most useful in addressing specific clinical concerns.
Occasional biopsies show extensive breakdown and bleeding that largely obscures the
cytologic details of the glands and stroma. Although it is usually possible to exclude neoplastic
processes in such cases, detailed assessment of the endometrium to determine the underlying
pathologic process becomes difficult. Unless the breakdown is clearly menstrual, i.e. reflecting
the shedding at the end of a normal ovulatory cycle, breakdown patterns should not be diagnosed
as “menstrual.” Instead, it is better to use descriptive diagnoses that reflect the morphologic
changes.
Descriptive diagnoses should be used carefully, however. The term “dyssynchronous”
endometrium has been used to describe apparent alterations in secretory phase development yet
this term does not have a specific connotation or meaning. Its use can be confusing unless there
is clear communication between the pathologist and gynecologist regarding its meaning, and I
don’t use it. Likewise, the terms “withdrawal” and “breakthrough” should be avoided in
pathologic diagnoses because they lack clear definitions in the clinical literature regarding
endometrium bleeding. It is best to avoid other vague terms such as “lytic endometrium.”
In summary, the endometrial biopsy showing benign, non-hyperplastic changes presents a
distinct group of challenges for the pathologist. A myriad of normal and pathologic processes
with varied histology may be encountered. In the absence specific lesions such as endometritis,
polyp or hyperplasia, a descriptive evaluation that clearly describes the changes present will help
guide the gynecologist in patient management.
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TABLE 1
POSSIBLE CAUSES OF ABNORMAL SECRETORY PHASE PATTERNS
Luteal phase defects
Persistent corpus luteum (irregular shedding)
Organic lesions (polyps, secretory hyperplasia, etc.)
Submucosal leiomyomas
Intrauterine adhesions
Inflammation
Complications of pregnancy
Progestin effects
TABLE 2
HISTOLOGIC FEATURES OF BREAKDOWN AND BLEEDING
Stromal “collapse” with cell clusters
Eosinophilic syncytial change
Fibrin thrombi
Nuclear debris at base of gland cells
Nuclear debris in stroma
Hemosiderin
Foam cells
Stromal fibrosis and hyalinization
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TABLE 3
FEATURES OF ENDOMETRIAL EPITHELIAL ATYPIA
Nuclei enlarged, irregular
Loss of nuclear polarity
Chromatin clumping (vesicular appearance)
Prominent nucleoli
Cytoplasmic eosinophilia, diffuse or focal
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Reference List
(1) Mazur MT, Kurman RJ. Diagnosis of endometrial biopsies and curettings. A practical
approach. New York: Springer Science+Business Media, 2005.
(2) Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. 6 ed.
Baltimore: Lippincott Williams & Wilkins, 1999.
(3) Butler WJ. Normal and abnormal uterine bleeding. In: Rock JA, Jones HW, III, editors.
Te Linde's operative gynecology. Philadelphia: Lippincott Williams and Wilkins, 2003:
457-481.
(4) Galle PC, McRae MA. Abnormal uterine bleeding. Finding and treating the cause.
Postgrad Med 1993; 93:73-81.
(5) Kilbourn CL, Richards CS. Abnormal uterine bleeding. Diagnostic considerations,
management options. Postgrad Med 2001; 109(1):137-4, 147.
(6) Stenchever MA. Differential diagnosis of major gynecologic problems by age groups. In:
Stenchever MA, Droegemueller W, Herbst AL, Mishell DR, Jr., editors. Comprehensive
gynecology. St. Louis: Mosby, Inc., 2001: 155-177.
(7) Wren BG. Dysfunctional uterine bleeding. Aust Fam Physician 1998; 27(5):371-377.
(8) Aksel S, Jones GS. Etiology and treatment of dysfunctional uterine bleeding. J Obstet
Gynecol 1974; 44:1-13.
(9) Altchek A. Dysfunctional uterine bleeding in adolescence. Clin Obstet Gynecol 1977;
20:633-650.
(10) Bayer SR, DeCherney AH. Clinical manifestations and treatment of dysfunctional uterine
bleeding. JAMA 1993; 269:1823-1828.
(11) Scommegna A, Dmowski WP. Dysfunctional uterine bleeding. Clin Obstet Gynecol
1973; 16:221-254.
(12) Vakiani M, Mawad J, Talerman A. Heterologous sarcomas of the uterus. Int J Gynecol
Pathol 1982; 1:211-219.
(13) Buckley CH, Fox H. Biopsy pathology of the endometrium. London: Arnold, 2002.
(14) Dallenbach-Hellweg G. Histopathology of the endometrium. 4 ed. New York: SpringerVerlag, 1987.
(15) Sherman ME, Mazur MT, Kurman RJ. Benign diseases of the endometrium. In: Kurman
RJ, editor. Blaustein's pathology of the female genital tract. New York: Springer-Verlag,
2002: 421-466.
(16) Vakiani M, Vavilis D, Agorastos T, Stamatopoulos P, Assimaki A, Bontis J.
Histopathological findings of the endometrium in patients with dysfunctional uterine
bleeding. Clin Exp Obstet Gynecol 1996; 23(4):236-239.
(17) Ferenczy A. Pathophysiology of endometrial bleeding. Maturitas 2003; 45(1):1-14.
(18) Picoff RC, Luginbuhl WH. Fibrin in the endometrial stroma: Its relation to uterine
bleeding. Am J Obstet Gynecol 1964; 88:642-646.
(19) Stewart CJ, Campbell-Brown M, Critchley HO, Farquharson MA. Endometrial apoptosis
in patients with dysfunctional uterine bleeding. Histopathology 1999; 34(2):99-105.
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(20) Silverberg SG, Kurman RJ. Tumors of the uterine corpus and gestational trophoblastic
disease. Atlas of tumor pathology, 3rd series, Fascicle 3. Washington, DC: Armed Forces
Institute of Pathology, 1992.
(21) Zaman SS, Mazur MT. Endometrial papillary syncytial change. A nonspecific alteration
associated with active breakdown. Am J Clin Pathol 1993; 99:741-745.
(22) Norimatsu Y, Shimizu K, Kobayashi TK, Moriya T, Kaku T, Tsukayama C et al.
Endometrial glandular and stromal breakdown, part 2: cytomorphology of papillary
metaplastic changes. Diagn Cytopathol 2006; 34(10):665-669.
(23) Clement PB. Pathology of the uterine corpus. Hum Pathol 1991; 22:776-791.
(24) Shah SS, Mazur MT. Endometrial eosinophilic syncytial change related to breakdown.
Immunohistochemical evidence suggests a regressive process. In press . 2007.
(25) Hendrickson MR, Kempson RL. Endometrial epithelial metaplasias: proliferations
frequently misdiagnosed as adenocarcinoma. Report of 89 cases and proposed
classification. Am J Surg Pathol 1980; 4:525-542.
(26) Moritani S, Kushima R, Ichihara S, Okabe H, Hattori T, Kobayashi TK et al.
Eosinophilic cell change of the endometrium: a possible relationship to mucinous
differentiation. Mod Pathol 2005; 18(9):1243-1248.
(27) Horree N, Heintz AP, Sie-Go DM, van Diest PJ. p16 is consistently expressed in
endometrial tubal metaplasia. Cell Oncol 2007; 29(1):37-45.
(28) Miranda MC, Mazur MT. Endometrial squamous metaplasia. An unusual response to
progestin therapy of hyperplasia. Arch Pathol Lab Med 1995; 119(5):458-460.
(29) Wheeler DT, Bristow RE, Kurman RJ. Histologic alterations in endometrial hyperplasia
and well-differentiated carcinoma treated with progestins. Am J Surg Pathol 2007;
31(7):988-998.
12
BENIGN ENDOMETRIUM:
DYSFUNCTIONAL BLEEDING,
BREAKDOWN, AND
METAPLASIA
Michael T. Mazur, M.D.
ClearPath Diagnostics
Syracuse, NY
mmazur@clearpathdiagnostics.com
AUB: Most Common
• Dysfunctional bleeding
• Polyps
• Atrophy
Abnormal Uterine Bleeding:
Sentinel of Endometrial Pathology
• Dysfunctional
• Organic lesions
– Polyps, Hyperplasia, Carcinoma, etc.
•
•
•
•
•
Atrophy
Exogenous hormones
Complications of pregnancy
Inflammation
Systemic bleeding disorders
Dysfunctional Uterine Bleeding
• Abnormal bleeding with no organic
cause
• Pathogenesis:
A. Anovulatory cycles
B. Luteal phase abnormalities
1. Luteal phase defect
2. Irregular shedding
Anovulatory Cycles
Anovulatory Bleeding
• Follicles develop, but no
ovulation with rupture
• Estradiol production leads to
endometrial proliferation
• Variable atresia or persistence
of follicle
• Follicles involute
No
estrogen, withdrawal bleeding
• Follicles persist
Estrogen
production, vascular ectasia,
breakthrough bleeding
Anovulatory Bleeding Pattern
• Proliferative phase glands and
stroma, variable amount
• Glands may have slight
disorganization (disordered)
• Glandular and stromal
breakdown, focal to diffuse
Proliferative with partial breakdown
Fibrin thrombi and stromal collapse
Proliferative with focal breakdown
Anovulatory bleeding pattern with marked fragmentation
Disordered Proliferative
Phase Pattern
• Mildly irregular gland shapes
and sizes
• May be result of anovulatory
cycles
• Diagnosis often over-used
Luteal Phase Defect
• Inadequate progesterone
production from corpus luteum,
possibly due to premature
regression
• Associated with infertility
• Role in DUB poorly defined
Histologic Features Of LPD
• Histologic date lags by more
than 2 days, or possibly
• Irregular maturation, or
• Non-menstrual secretory with
breakdown
Secretory with irregular maturation
Secretory with irregular maturation
Secretory bleeding pattern
Causes of Abnormal Secretory
Phase Development
• Luteal phase abnormalities
• Organic lesions
– Polyps, secretory hyperplasia, etc.
•
•
•
•
Leiomyomas
Adhesions
Chronic inflammation
Progestin effects
Secretory bleeding pattern
Non-menstrual Breakdown
(Bleeding Pattern)
• Pattern of early necrosis of the
endometrium
• Specific and unique morphologic
features
• Changes along with fragmentation
can mimic other lesions
Breakdown with artifactual crowding
Breakdown And Bleeding
•
•
•
•
•
Stromal “collapse” with clusters
Nuclear debris (apoptosis)
Fibrin thrombi
Eosinophilic syncytial change
Hemosiderin, foam cells,
hyalinized stroma
Complex hyperplasia
Eosinophilic Syncytial
Change
Eosinophilic Syncytial
Change
• Syncytial aggregates of pink
epithelium
• Usually along surface
epithelium
• Cytologically bland
• Can form pseudo-papillary tufts
• A marker of endometrial
breakdown in a variety of
conditions, many not
hyperplastic or neoplastic
• Regressive change unrelated to
“metaplasia”
Focal breakdown with ESC and stromal clusters
Anovulatory bleeding pattern with ESC and stromal clusters
Proliferation Comparison
Ki-67
pHH3
ESC
1.3%
0
AH
15.8%
2.3%
Gr 1 CA
10.6%
2.4%
Ki-67: MIB-1 antibody
pHH3 = phospho-histone H2 Ser 28 (mitosis marker)
Extensive breakdown with ESC and pseudo-papillary pattern
Endometrial Cytoplasmic
Changes (Metaplasia)
•
•
•
•
•
Squamous
Ciliated cell (tubal)
Eosinophilic (pink cell)
Mucinous
Secretory (clear cell)
Eosinophilic (Pink)
Epithelial Cells
•
•
•
•
•
•
•
Atypical hyperplasia
Adenocarcinoma
Squamous differentiation
Ciliated cell change
Eosinophilic change
Mucinous change
Eosinophilic syncytial
change (ESC)
Endometrial Cytoplasmic
Change (Metaplasia)
• Usually an estrogenic effect
• May be due to irritation or trauma,
e.g., polyp or inflammation
• Often associated with hyperplasia or
carcinoma; amplified with progestin
therapy
Atypical Hyperplasia
Diagnostic Features
• Cytologic atypia, focal or diffuse.
Irregular nuclei with chromatin
clumping and prominent nucleoli
• Loss of nuclear polarity
• Cytoplasm abundant with dense
eosinophilia, focal or diffuse
Ciliated/Eosinophilic
Cell Change
• Nuclei often round, stratified
• Smaller, uniform nuclei without
chromatin changes, nucleoli of
atypical cells
• Luminal border usually sharp
Atypical hyperplasia
Ciliated cell change in simple hyperplasia
Eosinophilic cell change in benign polyp
Mucinous Change
• Variable presentation: from
simple endocervical-type
epithelium to complex patterns
• Eosinophilic change related to
mucinous change in some
cases.
Mucinous change in hyperplasia without atypia
Eosinophilic and mucinous change in hyperplasia
Squamous Change
(Squamous Differentiation)
• Seen in polyps, hyperplasia,
carcinoma, inflammation
• Often non-keratinizing
• Luminal clusters (morules)
gives crowded gland pattern
Benign polyp with squamous metaplasia
Complex atypical hyperplasia with squamous change
Complex atypical hyperplasia with squamous change
Well-differentiated adenocarcinoma with squamous change
Metaplasia
(Cytoplasmic Change)
Common Concerns
• Occur in a variety of conditions,
often hyperplasia or polyp
• ESC is not related to
“metaplasia”
• Evaluate cytologic detail to
separate from significant atypia
• Is the specimen representative
and adequate?
• Is hyperplasia, atypia or
carcinoma present?
• Abnormal, but benign - what is
the best diagnosis?
The Report: Abnormal, Benign and
Difficult to Classify
• Exclude other pathology, e.g.,
polyps, hyperplasia, atypia, etc.
• Minimize comments about
metaplasia/cytoplasmic change
• Diagnose descriptively
Descriptive Diagnoses,
Examples
• Proliferative with glandular and
stromal breakdown
• Abnormal secretory bleeding
pattern
• Secretory with irregular maturation
(Avoid: “breakthrough,” “withdrawal,”
“dyssynchronous,” “lytic”, etc.)
ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA
George L. Mutter MD
Associate Professor of Pathology, Harvard Medical School
Div. of Women's and Perinatal Pathology, Department of Pathology
Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115
website: www.endometrium.org
Biology of Endometrial Intraepithelial Neoplasia 1
Endometria Intraepithelial Neoplasia (EIN) is a clonal proliferation of architecturally and
cytologically altered premalignant endometrial glands which are prone to malignant transformation
to endometrioid (Type I) endometrial adenocarcinoma. EIN lesions are non-invasive genetically
altered neoplasms which arise focally, and may convert to malignant phenotype upon acquisition of
additional genetic damage. Diagnostic criteria for EIN have been developed by histopathologic
correlation with clinical outcomes, molecular changes, and objective computerized
histomorphometry.
EIN should not be confused with unrelated serous intraepithelial carcinoma (serous EIC),
which is an early phase of (Type II) papillary serous adenocarcinomas of the endometrium.
Management of EIN lesions follows guidelines long established for atypical endometrial
hyperplasia. A high concurrent cancer rate (26%), and concern that sampling errors may miss an
occult tumor, have led to a prevailing view that immediate hysterectomy is justified by its
combined diagnostic and therapeutic benefits. Young patients wishing to preserve fertility, and
women who are poor surgical risks, are candidates for hormonal (progestin) therapy. Systemic
progestins can successfully ablate up to 90% of endometrial precancers in young women 2,
although it is not possible in advance to predict that fraction which will respond. A decision to
treat hormonally must thus be made between the clinician and patient in full light of the risks, and
with the precondition that regular followup surveillance can be performed.
Figure 3: Clonal Origin of EIN. The first genetic changes (such as PTEN inactivation) which
Malignant
Transformation
Initiation
Normal Histology
EIN
Adenocarcinoma
(Polyclonal ? Latent “Clone”)
(Monoclonal
Premalignant Neoplasm)
(Monoclonal Malignant Neoplasm)
initiate endometrial carcinogenesis are unaccompanied by any phenotypic alterations at the light
microscopic level. This “latent”, phase of cytologically and architecturally normal but genetically
altered cells may persist for years in a normally menstruating woman. Low cancer risk, combined
with lack of a rational therapeutic response, are reasons that systematic screening and treatment of
these “latent” phase lesions is unwarranted at present. As additional genetic damage accumulates,
higher risk morphologically altered mutant clones declare themselves by demonstrating those
architectural and cytologic alterations that distinguish EIN. Malignant transformation of EIN
lesions, which occurs at least 46-times more frequently than non-EIN tissues, warrants careful
diagnosis and treatment. Endocrine modifiers of endometrial cancer risk act upon the latent and
EIN phases of this sequence by tipping the balance of clonal expansion vs. involution.
A combined molecular and histopathologic model for EIN:
Latent, premalignant, and malignant phases of EIN-mediated endometrial carcinogenesis
are diagrammed in Figure 3. In almost half of apparently normal women, histologically
unremarkable proliferative endometria contain a small fraction of (PTEN tumor suppressor gene)
mutant endometrial glands. This phase may be construed as “latent” because not only do the
mutated glands look completely normal under the microscope, but they progress to EIN and cancer
at very low efficiency. This latent phase may persist for years, with continued presence of scattered
and interspersed mutant glands after many menstrual cycles 3. Mutant glands are probably
represented in the reserve population of cells that regenerate a new functionalis each month.
Endocrine factors act upon these “latent precancers” to modulate involution, or progression to EIN.
Transition to EIN requires accumulation of additional genetic damage in at least one “latent
precancer” cell, which then clonally expands from its point of origin (indicated by expanding
arrows) to form a contiguous grouping of a tightly packed and cytologically altered glands
recognizable as EIN. The monoclonal precancer (EIN) develops internal heterogeneity through
mutation, and advantageous events selected by local conditions result in hierarchical subclones (left
to right) of varying success. EIN lesions have only marginal increases in growth potential, and
retain susceptibility to further growth modulation by hormonal factors. Some involute. Others,
through additional mutation and selection, reach a stage where hormonal support is no longer
required for survival. Malignant transformation to cancer is defined by accumulation of sufficient
genetic damage to permit invasion of adjacent stromal tissues.
1.What Is EIN?
Endometrial Intraepithelial Neoplasia, EIN 4;5, is the histopathologic presentation of
premalignant endometrial disease which confers an elevated risk for endometrial cancer. The
singular category of EIN is not stratified or divided into subgroups, and must be distinguished from
earlier phases of latent premalignant disease, and endometrial carcinoma. This term was proposed
by The Endometrial Collaborative Group 4 to accommodate changing concepts of premalignant
endometrial disease and take advantage of revised diagnostic strategies.
EIN needs to be treated, and the type of therapy decided between the patient and treating
physician. Things that may influence the choice of surgical vs. hormonal therapy include but are
not limited to: diagnostic confidence that a co-existing carcinoma has been excluded, desire for
maintained fertility, ability to perform followup surveillance, and patient-specific hormonal and
surgical risks.
2.Clinicopathologic Foundations Of EIN
Rigorous experimental validation of clinically and biologically defined endometrial
precancers, and development of correlative diagnostic criteria is a multidisciplinary process. Key
predictions expected of precancers 6 which have now been fulfilled for EIN, and practical aspects
of their clinical implementation are listed in Table III:
Table III: Precancer postulates fulfilled for EIN
Postulate
Precancers differ from normal tissues
Precancers share some, but not all features with
carcinoma
Precancers can be diagnosed
Precancers increase risk for carcinoma
Epidemiologic and genetic mechanisms are
linked
Introducing precancer genotype into an animal
produces premalignant lesions and heightened
cancer risk
Evidence
Monoclonal 7-9.
Divergent genotype 10.
Including PTEN 11-13, K-ras 14-16, and MLH1
changes 17.
Both are monoclonal 7-9;18.
Precancer-cancer lineage hierarchy 10.
Computerized morphometry reference standard
for EIN 18
High concurrent cancer rate in EIN 19;20;20
High future cancer rate in EIN 21-24
The PTEN gene, mutated in EIN, is subject to
hormonal modulation 13;25
100% of PTEN mutant heterozygote mice get
endometrial “hyperplasia” and 21% evolve to
carcinoma. 26
3.WHO Hyperplasia-EIN Concordances
Concordances with EIN diagnostic system and were obtained by review of cases initially
diagnosed using other endometrial hyperplasia
Complex
Simple
classification schemes 21.
Atypical
Non-Atypical
Non-Atypical
Figure 4: Correlation of WHO and EIN Diagnoses.
Gray portions of Bar Graphs show approximate
percentages of each WHO hyperplasia class that will be
diagnosed as EIN. Remaining WHO hyperplasias not
diagnostic of EIN (white) will be allocated to unopposed
estrogen (anovulatory), polyp, and other categories. Pie
chart shows relative contributions of each hyperplasia
type to the EIN diagnostic category in a series of 97 cases
with 28 EIN examples 21.
Hyperplasia
Hyperplasia
78%
44%
Hyperplasia
4%
29%
7%
4.Clinical Cancer Outcomes Following EIN Diagnosis
64%
The risk of developing endometrial cancer, as
predicted by an EIN diagnosis are the basis for therapy.
Endometrial Intraepithelial Neoplasia
Although there are many previous references citing cancer
outcomes of EIN patients 19;22;23, the two studies summarized below show cancer predictive value
of subjective (Figure 5) 21 and objective histomorphometric (Figures 6-8) 20 EIN diagnosis.
Patients with EIN lesions have an overall 89-fold increased cancer risk than those without EIN. In
practice, the time interval separating EIN from cancer divides these into either concurrent EIN and
cancer, or progression events from EIN to cancer. For purposes of illustration we have considered
cancers diagnosed within 12 months of EIN to be “concurrent” (Figure 7), and those following EIN
by more than one year to be “progression events” (Figure 8).
Figure 5: Cancer outcomes (black), by
followup interval (vertical axis) of 97
endometrial biopsies diagnosed by WHO
hyperplasia (left) or EIN (right) schema
21
. Endometrial hyperplasias (left panel)
were rediagnosed subjectively (without
morphometry) as EIN or benign, non-EIN
(right panel). All 8 cancer outcomes (black
symbols) followed an initial diagnosis of
EIN. EIN has a better negative predictive
value than atypical hyperplasia, as 2/8
cancer occurrences were seen in the nonatypical hyperplasia groups.
Hyperperplasia Schema
EIN Schema
Followup Interval, Days
2000
1500
1000
500
0
Outcome
No Cancer
Cancer
le x
mp al
Co pic
aty
1.0
Cancer Free Survival
Figure 6: Overall cancer free survival of 674
patients with “endometrial hyperplasia”
stratified by morphometry into EIN (D-Score
<1) or benign non-EIN (D-Score>1) 20. 65/67
cancer occurrences occurred in the EIN category.
Elevated cancer risk of having an EIN lesions is
89 times that of women without EIN. Incidences
of carcinoma following EIN diagnosis may be
considered concurrent (steep part of curve in
months 1-12) or future (more shallow curve > 12
months). These subsets of short and long term
cancer occurrences are plotted for this dataset in
Figures 3 and 4. 2/446 non-EIN and 65/228 EIN
cases developed adenocarcinoma.
lex
ple pia
mp pia
Sim aty
Co aty
no
no
n,
n ig I N
Be n-E
No
N
EI
Benign (DS>1)
0.8
0.6
0.4
EIN (DS<1)
0.2
HR=89
0.0
0
50
100
150
Followup Time, Months
200
1.0
Benign (DS>1)
0.8
Cancer Free Survival
Figure 7: Concurrent Cancer in women
with EIN. “Concurrent cancers,” those
diagnosed within 1 year of a baseline
cancer-free endometrial biopsy, are more
likely to be seen in women with EIN
compared to women without EIN.
Approximately half of patients with EIN
lesions will have a cancer diagnosed in the
first year. 197 Women with “endometrial
hyperplasia restratified into EIN vs. nonEIN categories. 0/87 non-EIN and 43/110
EIN cases developed adenocarcinoma.
0.6
0.4
EIN (DS<1)
0.2
0.0
0
5
10
15
Followup Time, Months
Figure 8: Long term cancer
progression in women with EIN 20.
Cancer outcomes that occur more than
one year after EIN diagnosis are bonafide progression events from a
premalignant to malignant phase of
disease. Progression to cancer more
than one year following EIN diagnosis
is 45 times more likely compared to
women without EIN. Note the tempo
of cancer appearance indicates that it
can take years for an EIN to evolve into
adenocarcinoma.. 477 Women with
“endometrial hyperplasia restratified
into EIN vs. non-EIN categories. 2/359
non-EIN and 22/118 EIN cases
developed adenocarcinoma.
Cancer Free Survival
1.0
Benign (DS>1)
0.8
0.6
EIN (DS<1)
0.4
0.2
HR=45
0.0
0
\\
50
100
150
Followup Time, Months
200
5.How Is EIN Diagnosed?
(also see www.endometrium.org)
EIN is diagnosed by a pathologist using routine (hematoxylin and eosin stained) sections
prepared from a representative endometrial sample 27;28. It is extremely important to note that
diagnostic accuracy may be severely compromised by exogenous progestin-containing hormonal
therapies. For this reason, primary diagnosis or followup surveillance of a suspected EIN lesion
should be based whenever possible on a sample obtained while the patient is not on therapeutic
hormones. For those patients on progestins, diagnostic tissue can be obtained 2-4 weeks after
stopping exogenous hormones, after completion of a withdrawal bleed. Although computerized
morphometry has been a useful tool in identifying features characteristic of EIN, such equipment is
not required for routine diagnosis. Rather, pathologist interpretation of stated criteria at a standard
microscope is adequate.
It should be noted that EIN is a precursor of endometrioid endometrial adenocarcinomas
and is unrelated to the "Endometrial Intraepithelial Carcinoma" proposed 29 to be the earliest stages
of papillary serous type endometrial adenocarcinomas.
A framework for EIN Diagnosis is shown in Table I at the beginning of this sylabus.
Notable is the clear separation of endometrial changes caused by unopposed estrogens, and
carcinoma, from EIN.
1.Topography of EIN
The distribution of a lesion is useful in distinguishing between the diffuse, field-wide
effects, of an abnormal hormonal environment (anovulation, or persistent estrogen effect), surface
changes secondary to stromal breakdown, and more focal EIN. Clonal origin from a single cell
requires EIN lesions to begin as local processes within the endometrial compartment. Early EIN
lesions are easily diagnosed by their contrast in architecture and cytology with the background from
which they have emerged. Over time, EIN lesions may completely overrun the background
endometrium, thereby removing the convenient lesion-to-background contrast in morphology
which assist in EIN diagnosis. For this reason, or because of fragmentation, many EIN lesions
must be diagnosed without the benefit of comparison with companion benign tissues. Exclusion of
artifact and careful evaluation of the architectural and cytologic features of EIN usually permits
accurate diagnosis in these instances.
2.EIN Diagnostic Criteria
All of the diagnostic criteria of Table IV, listed as A-E below, must be met in order to make
an EIN diagnosis. The entire slide should first be scrutinized under low magnification for
localizing lesions, and if found, these areas examined under higher power to assess possible
changes in cytology within the architecturally distinct focus. Widespread EIN lesions that have
replaced the entire endometrial compartment tend to have a sufficiently atypical cytology that
background normal endometrium is no longer required as a reference point for accurate diagnosis.
Size, architecture, and cytology features are easy EIN diagnostic criteria. Much more
difficult are exclusion of benign mimics and adenocarcinoma from the differential diagnosis. There
are no simple rules for benign mimic exclusion. The broad universe of competing entities can only
be recognized on sight by one who has the easy familiarity that comes with experience. Consistent
demarcation of the EIN-adenocarcinoma threshold remains important clinically because it provides
a basis for the clinician to evaluate the risks of electing hormonal rather than surgical therapy in
younger patients who wish to retain fertility.
Special diagnostic challenges, such as recognition of EIN within polyps, interpretation of
subdiagnostically small or fragmented lesions, and interpretation of lesions with non-endometrioid
differentiation have specific caveats presented below that should be carefully studied.
Table IV: EIN Diagnostic Criteria. Modified after 5.
EIN Criterion
Architecture
Cytology
Size >1 mm
Comments
Area of Glands greater than Stroma
Cytology differs between architecturally crowded focus and background, or
clearly abnormal.
Maximum linear dimension exceeds 1mm.
Exclude mimics
Benign conditions with overlapping criteria: Basalis, secretory, polyps,
repair, etc..
Exclude Cancer
Carcinoma if mazelike glands, solid areas, polygonal “mosaic-like” glands,
myoinvasion, or significant cribriforming
a.Architecture: Gland area exceeds stromal area:
A cardinal architectural feature of endometrial precancers is glandular crowding, with a
threshold quantitative cutoff for EIN lesions of less than half of the tissue area occupied by stroma
(Volume Percentage Stroma). Areas with large dominant cysts should always be avoided in
making this assessment. Although EIN is an epithelial disease, visual assessment of the glands
themselves is complicated by frequent artifactual displacement from associated stroma, pale
staining of most epithelia, and visual "shimmering" between gland epithelia and lumens. These
may all be avoided by focusing on the stromal compartment which has the significant advantages of
a more uniform composition throughout the specimen, and superior staining qualities. By focusing
on the stroma itself only intact fragments in which stroma has not been avulsed from glands will be
evaluated.
Careful review of graphic and histologic examples of varying stromal densities will assist in
training your eye to classify patient material as above or below the diagnostic threshold. EIN
lesions tend to cluster with a median volume percentage stroma of about 40% and non-EIN
(benign) lesions cluster at a median of approximately 75%. These differences are sufficiently
great that visual assessment by a trained eye can be informative.
b.Cytology of architecturally crowded area is different than background, or clearly
abnormal:
There is no absolute standard for cytologic features of EIN lesions, but the cytology of EIN
is usually clearly demarcated as divergent from that of co-existing benign endometrial tissues in the
same patient. The manner of cytologic change in EIN varies considerably from patient to patient,
and can include but not be limited to, increased variation in nuclear size and contour, clumped or
granular chromatin texture, change in nucleoli, change in nuclear/cytoplasmic ratio, and altered
cytoplasmic differentiation. Stereotypical static descriptions of cytologic atypia, such as nuclear
rounding and appearance of nucleoli are met in many but not all EIN lesions. In this sense, a fixed
presentation of cytologic atypia is not a prerequisite for EIN. Attempts to define an absolute
standard are confounded by the extreme morphologic plasticity of endometrial glandular cells
under changing hormonal, repair, and differentiation conditions.
Cytologic changes in some EIN lesions are manifest as a change in differentiation state to a
tubal, mucinous, micropapillary, or eosinophilic phenotype. These must be distinguished from the
scattered random pattern of hormonally, or surface located repair-induced “metaplasias.” Further
details of how to interpret non-endometrioid EIN lesions are presented in the “Pitfalls” section
below.
In those cases with no normal glands for internal reference, it is necessary to assess the
freestanding cytology of relevant fragments in the context of their architectural features. Some EIN
lesions occupy the entire tissue sample, and should not be underdiagnosed for lack of a convenient
benign gland in the area.
c.Size >1mm in maximum dimension:
Accurate EIN diagnosis requires a contiguous field of glands sufficiently large to enable
reliable assessment of architecture. A minimum lesion size of 1 mm maximum dimension was
required in the previous clinical outcome studies 19;20;22;24 for an EIN lesion to achieve elevated
cancer risk. That area of an EIN lesion which meets architectural (gland area) and cytologic
(changed) criteria for diagnosis must measure a minimum of 1mm in maximum dimension, a scale
which usually encompasses more than 5-10 glands. Most biopsy formats produce tissue fragments
in excess of 1.5-2mm. The size requirement must be met in a single tissue fragment, not added
amongst multiple fragments. There is no formal evidence that once beyond the minimum 1mm,
EIN lesions should be stratified by size, but if a lesion is discretely focal, it may be of interest to the
clinician to know what fraction of the available curettings contain lesion.
Individual or small clusters of cytologically altered glands have an undefined natural history
and are best diagnosed descriptively (See Pitfalls section below).
d.Exclusion of Benign Mimics
Patients with one of the conditions listed below may still have an EIN, but this diagnosis
should be made with careful consideration into how the coexisting factor(s) may modify the criteria
for EIN diagnosis. If a specimen is refractory to confident diagnosis, a comment as to the nature of
the problem may be useful in directing management.
1. Reactive changes caused by infection, physical disruption, recent pregnancy, or recent
instrumentation. These can cause piling up of the epithelium, and loss of nuclear polarity..
2. Artifactual gland displacement. Beware diagnosing an EIN lesion if the cytology is
identical between areas with crowded compared to uncrowded glands! Many of these are
artifactual disruptions where the stroma is sheared and glands pushed in apposition .
3. Persistent Estrogen Effect: Randomly scattered cysts of protracted estrogen exposure and
occasional branching glands are commonly encountered in anovulatory or estrogen-exposed
endometria. Gland density is uniformly irregular throughout the endometrial compartment,
with occasional clusters of glands having a cytology identical to the uncrowded areas.
These can be diagnosed as “Benign Endometrial Hyperplasia” if glands are significantly
crowded, or in some mild cases as "disordered proliferative" endometrium. With increasing
duration, microthrombi form and scattered stromal breakdown may be associated with
epithelial piling along the collapsed stromal surfaces.
4. Mid to late secretory endometrium displays loss of nuclear polarity, nuclear enlargement,
and variation in nuclear size which if measured objectively by computerized morphometry
overlaps substantially with EIN lesions. Stromal responsiveness to progesterone is not
homogenous at all endometrial depths. Lack of stromal pre-decidualization in the deeper
functionalis and superficial basalis makes glands appear crowded, and these same glands
may display a worrisome cytology and complicated saw-toothed luminal profiles
5. Endometrial polyps contain irregularly spaced glands in which scattered glands may differ
from native endometrium due to their tendency to have reduced hormonal responsiveness.
Benign polyps may also have low volume percentage stroma caused by cysts (senile polyps)
or random aggregations of glands. Approximately 10% of EIN lesions, however, will
present within an endometrial polyp and these must be diagnosed as described below in the
“Pitfalls” section.
6. Endometrial breakdown is one of the most common settings for overdiagnosis of a benign
endometrium as a precancer or cancer. Breakdown may follow an ovulatory or anovulatory
cycle and persist into the transitional period between late menses and early proliferative
endometrium. Altered cytology is due to piling up of epithelial cells unsupported by
stroma, and associated nuclear changes such as loss of polarity which may be accentuated
under certain fixation conditions which exaggerate chromatin texture (Bouin's fixative).
e.Exclusion of Carcinoma
Cancer may coexist with EIN in an individual patient, but should be always be separately
diagnosed because current management of carcinoma differs from that for EIN. Keep in mind that
absence of carcinoma in a tissue biopsy does not exclude the possibility of that the patient has a
cancer which was unsampled during the biopsy procedure. An opinion should always be rendered
based upon available material, and clearly stated.
EIN is composed of individual glands lined by an epithelium one cell layer thick. The
epithelium may be pseudostratified, but should not be cribriform or composed of solid areas of
epithelial cells. Presence of any of the following features involving neoplastic glands is
inconsistent with EIN, and a diagnosis of carcinoma should be entertained.
1. Meandering or “mazelike” lumens
2. Solid epithelium
3. Cribriform architecture.
4. “Mosaic” gland pattern of distorted polygonal glands with threadlike intervening stroma
Myoinvasion. Unfortunately, myometrium is rarely available for evaluation in a biopsy or
curettage specimen.
Reference List
1. Mutter GL, Zaino RJ, Baak JPA, Bentley RC, Robboy SJ. The Benign Endometrial
Hyperplasia Sequence and Endometrial Intraepithelial Neoplasia. Int J Gynecol
Pathol 2007; 26:103-114.
2. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and welldifferentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol
Surv 1997; 90(3):434-440.
3. Mutter GL, Ince TA, Baak JPA, Kust G, Zhou X, Eng C. Molecular identification of
latent precancers in histologically normal endometrium. Cancer Res 2001; 61:43114314.
4. Mutter GL, The Endometrial Collaborative Group. Endometrial intraepithelial
neoplasia (EIN): Will it bring order to chaos? Gynecol Oncol 2000; 76:287-290.
5. Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales F, Tavassoli FA.
Tumors of the uterine corpus: epithelial tumors and related lesions. In: Tavassoli FA,
Stratton MR, editors. WHO Classification of Tumors: Pathology and Genetics of
Tumors of the Breast and Female Genital Organs. Lyon, France: IARC Press, 2003:
221-232.
6. Berman JJ, bores-Saavedra J, Bostwick D et al. Precancer: A conceptual working
definition Results of a Consensus Conference. Cancer Detect Prev 2006; 30:387-
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
394.
Esteller M, Garcia A, Martinez-Palones JM, Xercavins J, Reventos J. Detection of
clonality and genetic alterations in endometrial pipelle biopsy and its surgical
specimen counterpart. Lab Invest 1997; 76:109-116.
Mutter GL, Chaponot M, Fletcher J. A PCR assay for non-random X chromosome
inactivation identifies monoclonal endometrial cancers and precancers. Am J Pathol
1995; 146:501-508.
Jovanovic AS, Boynton KA, Mutter GL. Uteri of women with endometrial carcinoma
contain a histopathologic spectrum of monoclonal putative precancers, some with
microsatellite instability. Cancer Res 1996; 56:1917-1921.
Mutter GL, Boynton KA, Faquin WC, Ruiz RE, Jovanovic AS. Allelotype mapping of
unstable microsatellites establishes direct lineage continuity between endometrial
precancers and cancer. Cancer Res 1996; 56:4483-4486.
Levine RL, Cargile CB, Blazes MS, Van Rees B, Kurman RJ, Ellenson LH. PTEN
mutations and microsatellite instability in complex atypical hyperplasia, a precursor
lesion to uterine endometrioid carcinoma. Cancer Res 1998; 58:3254-3258.
Maxwell G, Risinger J, Gumbs C et al. Mutation of the PTEN tumor supressor gene in
endometrial hyperplasias. Cancer Res 1998; 58:2500-2503.
Mutter GL, Lin MC, Fitzgerald JT et al. Altered PTEN expression as a diagnostic
marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924-930.
Duggan BD, Felix JC, Muderspach LI, Tsao J-L, Shibata DK. Early mutational
activation of the c-Ki-ras oncogene in endometrial carcinoma. Cancer Res 1994;
54:1604-1607.
Sasaki H, Nishii H, Takahashi H et al. Mutation of the Ki-ras protooncogene in human
endometrial hyperplasia and carcinoma. Cancer Res 1993; 53:1906-1910.
Mutter GL, Wada H, Faquin W, Enomoto T. K-ras mutations appear in the
premalignant phase of both microsatellite stable and unstable endometrial
carcinogenesis. Mol Pathol 1999; 52:257-262.
Esteller M, Catasus L, Matias-Guiu X et al. hMLH1 Promoter Hypermethylation Is an
Early Event in Human Endometrial Tumorigenesis. Am J Pathol 1999; 155(5):17671772.
Mutter GL, Baak JPA, Crum CP, Richart RM, Ferenczy A, Faquin WC. Endometrial
precancer diagnosis by histopathology, clonal analysis, and computerized
morphometry. J Pathol 2000; 190:462-469.
Dunton C, Baak J, Palazzo J, van Diest P, McHugh M, Widra E. Use of computerized
morphometric analyses of endometrial hyperplasias in the prediction of coexistent
cancer. Am J Obstet Gynecol 1996; 174:1518-1521.
Baak JP, Mutter GL, Robboy S et al. The molecular genetics and morphometrybased endometrial intraepithelial neoplasia classification system predicts disease
progression in endometrial hyperplasia more accurately than the 1994 World Health
Organization classification system. Cancer 2005; 103(11):2304-2312.
Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL. Prediction of
endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis.
Mod Pathol 2005; 18:324-330.
Baak JPA, Nauta J, Wisse-Brekelmans E, Bezemer P. Architectural and nuclear
morphometrical features together are more important prognosticators in endometrial
hyperplasias than nuclear morphometrical features alone. J Pathol 1988; 154:335341.
Orbo A, Baak JP, Kleivan I et al. Computerised morphometrical analysis in
endometrial hyperplasia for the prediction of cancer development. A long-term
24.
25.
26.
27.
28.
29.
retrospective study from northern Norway. J Clin Pathol 2000; 53(9):697-703.
Baak JP, Orbo A, van Diest PJ et al. Prospective multicenter evaluation of the
morphometric D-score for prediction of the outcome of endometrial hyperplasias. Am
J Surg Pathol 2001; 25(7):930-935.
Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Ziebold U, Eng C. Changes in
endometrial PTEN expression throughout the human menstrual cycle. J Clin
Endocrinol Metab 2000; 85:2334-2338.
Stambolic V, Tsao MS, Macpherson D, Suzuki A, Chapman WB, Mak TW. High
incidence of breast and endometrial neoplasia resembling human Cowden syndrome
in pten+/- mice. Cancer Res 2000; 60(13):3605-3611.
Mutter GL. Endometrial Intraepithelial Neoplasia: A new standard for precancer
diagnosis. Cont Ob Gyn 2001; 46:92-98.
Mutter GL. Histopathology of genetically defined endometrial precancers. Int J
Gynecol Pathol 2000; 19:301-309.
Ambros RA, Sherman ME, Zahn CM, Bitterman P, Kurman RJ. Endometrial
intraepithelial carcinoma: A distinctive lesion specifically associated with tumors
displaying serous differentiation. Hum Pathol 1995; 26:1260-1267.
International Society of Gynecological Pathologists Society Companion Meeting
United States and Canadian Academy of Pathology
March 2, 2008
Endometrial Cancer Precursor Lesions: WHO is Better (?)
Teri A. Longacre, MD
Associate Professor of Pathology
Stanford University Hospital & Medical Center
Stanford University School of Medicine
1
Endometrial Cancer Precursor Lesions: Discussion Points
Although there is little doubt that there are some forms of altered endometrial glandular
proliferations that, when present, pose an increased risk of adenocarcinoma, the histologic
definition of these risk lesions and their relative risk is the subject of ongoing controversy.
Despite the advances in molecular biology of endometrial neoplasia, our knowledge of
endometrial carcinoma and its precursor lesions is meager compared to precancer lesions in
the breast and colon, and unlike these latter two organ systems, the acquisition of new
knowledge is beset by formidable methodologic problems (3):
1) The morphologic definition of the target event (adenocarcinoma, usually grade 1
adenocarcinoma) is ill defined, subject to poor interobserver agreement, and a matter
of ongoing debate. We use myoinvasion as the target event in our definition of grade
1 endometrial adenocarcinoma (i.e., only those proliferations that have been
observed to be associated with myometrial invasion with significant frequency are
considered “adenocarcinoma” with other lesser degrees of glandular proliferation
considered “atypical” or “borderline”) (9).
2) Even if one were to use myoinvasive adenocarcinoma as the target event, the
morphologic definition of myoinvasion (particularly superficial myoinvasion and
adenocarcinoma involving adenomyosis) is subject to poor interobserver
reproducibility. Ideally, the definition of an endometrial precursor lesion would be
geared toward identifying those lesions that pose a significant risk for progression to
clinically significant adenocarcinoma- i.e., myoinvasive carcinoma – not (to borrow
a phrase used to designate very low risk lesions in the prostate) the pathologist’s
carcinoma.
3) Unlike other organ systems, the putative precursor lesions in the endometrium are
anatomically unstable; they can be shed spontaneously, or they can be reversed by a
change in the patient's hormonal milieu, whether through alterations in physiology
or alterations produced iatrogenically.
4) The endometrial sampling procedure is essentially a screening tool – not all of the
endometrium may be represented in any given sampling, regardless of the technique
and even when it is, the presence of a myometrial lesion cannot be assessed. Most
pathologists and surgeons assume the presence of cancer in the myometrium
(myoinvasive cancer) is associated with cancer in the endometrium. Fortunately, this
is often the case, but there are occasional cancers that invade without an appreciable
exophytic component (much like some invasive colorectal cancers in patients with
longstanding ulcerative colitis).
5) Another unique feature of endometrial glandular proliferations is the variety of
altered cytoplasmic differentiation or metaplastic patterns that commonly occur in
both benign, precursor and cancer lesions. Since some of these altered
differentiation patterns exhibit slightly more cytologic atypia than that which is
2
associated with standard endometrioid differentiation, definitions of precursor
lesions must take into account this variable cytologic appearance. For example,
ciliated change typically contains rounder nuclei, often with small nucleoli, and
some of the problems with earlier definitions of atypical hyerplasia failed to take this
into account. (A similar problem presents itself in the breast with apocrine lesions.)
6) Given the absence of evidence-based and consensus-driven diagnostic criteria, there
is a perception that existing criteria for the diagnosis of endometrial cancer and its
precursor lesions suffer from such poor reproducibility, that the willingness of the
surgeon and patient to retain the organ involved by any putative precancerous lesion
to wait out its natural history is low, particularly in the usual age group in which
these lesions develop.
7) The use of surrogate markers (such as PTEN in the proposed endometrial
intraepithelial neoplasia scheme) to inform our morphologic definitions of precancer
and cancer must meet minimum criteria required for the use of a surrogate marker in
other organ systems: i.e., be sensitive and specific, reproducible, and subject to
independent confirmation.
8) Current terminology and definitions for endometrial precursor lesions are imprecise,
but the introduction of new terminology should be conducted with caution. For
example, the concept of “intraepithelial” is at best imprecise in the endometrium,
given the absence of a bona fide basement membrane (such as is seen in the cervix),
and at worst erroneous, given the emerging recognition in other organ systems of
apparent shared properties of some in situ and invasive cancers.
WHO Is Best?
The WHO criteria for endometrial cancer precursor lesions are based on the study by
Kurman and colleagues in 1985 (7). In that study, the risk of progression to carcinoma
was 23% for atypical endometrial hyperplasia, whereas it was only 2% for non-atypical
hyperplasia. Although the target lesion in this study was “carcinoma” and not
“myoinvasive adenocarcinoma,” we know from previous studies that the definition(s)
used for carcinoma in that study are, with minor exceptions, a reasonable stand-in for
myoinvasive grade 1 endometrial cancer (9)
The histologic criteria for complex atypical hyperplasia that were used in that study are
well recognized and included a variety of cytologic and architectural features: nuclear
enlargement, nuclear rounding, nucleoli, abnormal chromatin distribution (either dispersed
or clumped), some degree of pleomorphism, loss of nuclear polarity, and a shift in the
nuclear-to-cytoplasmic ratio in favor of the nuclei. The relative size of the nuclei was
estimated by comparing them to the surrounding stromal cell nuclei or those of residual
3
normal epithelial elements. Mitotic figures were almost always present in atypical
hyperplasia and often numerous, but abnormal division figures were sparse or absent. In the
study published by Kurman and associates, once a patient had atypical hyperplasia, no
further insight into risk was provided by grading the degree of atypia; that is, varying
degrees of cytologic atypia were not reflected in a greater or lesser risk of adenocarcinoma
once it was determined that the endometrium was architecturally complex and the glands
were lined by cytologically atypical cells (6). This is not unexpected, given the narrow range
of atypia that is present in these lesions.
Subsequent reports using the Kurman criteria, provide additional evidence that
approximately 20% to 30% of women with endometrial hyperplasia characterized by glands
with marked architectural complexity and crowding, in addition to cytologic atypia, progress
to a pattern that the investigators deemed morphologic adenocarcinoma (4). That is to say,
not all precancers appear to progress to malignancy, either in the form of myoinvasion or
clinical relapse, but a significant and diagnostic reproducible proportion do so despite the
inherent difficulties in this diagnostically difficult range of endometrial glandular
proliferations.
Although the World Health Organization, which is largely based on data from the Kurman
et al study, proposes a four-tiered classification, in most workers’ experience, the vast
majority of cytologically atypical lesions are architecturally complex and therefore, the
degree of cytologic atypia, despite its inherent reproducibility problems, may well be the
best discriminator for precancer in this range of glandular proliferation.
The degree of interobserver agreement for the diagnosis of “atypical hyperplasia” has been
addressed by Kurman and coworkers (6). In that study, the only cytologic feature that was
strongly associated with distinguishing hyperplasia (low risk for progression) from atypical
hyperplasia (significant risk for progression) was the presence of nucleoli. The overall
reproducibility for the diagnosis of “atypical hyperplasia” was moderate (kappa = 0.36 to
0.54) (6), while the overall reproducibility for the diagnoses of “hyperplasia” and “grade 1
carcinoma” were substantial. The interobserver reproducibility using the WHO criteria was
more variable due to the use of 4 categories as opposed to 2, but was moderate overall and
did not exceed that for the 2 category classification. Despite the utility of nucleoli in
reproducibly distinguishing “hyperplasia” from “atypical hyperplasia” in that study,
consensus diagnosis was achieved using a variety of pathways, not all of which entailed a
conscious assessment for the presence of nucleoli (6). An experiential component combined
with integration of multiple simultaneous evaluations appears to be inherent in the process
of evaluating endometria for the presence of a risk lesion. Since the 2 tiered classification
system of “hyperplasia” and “atypical hyperplasia” appears to perform as well as the 4 tiered
WHO classification, the use of the 2 tiered system would appear to be preferable.
Can We Do Better?
4
To appropriately answer the question as to what is the best method of diagnosing precancer
in the endometrium, one has to pose the question: to what end? For the purposes of
generating a molecular-based understanding of endometrial carcinogenesis, a classification
scheme based on molecular correlates is of obvious scientific and possibly, epidemiologic
value. For the purposes of clinical decision making, any taxonomic scheme that is used to
classify precancer in the endometrium should reflect what is known about cancer risk – i.e.,
myoinvasive, clinically significant cancer risk. Ideally, the two end-points are
complementary, but experience has shown that this is often not the case and standard
histologic criteria based on outcome remain the gold standard. In absence of a carefully
defined and consensus-driven target lesion to assess outcome and hence, inform our
diagnostic criteria for endometrial cancer and precancer, studies such as those recently
published from the GOG that reported a dismally and unacceptably low level of pathologist
reproducibility for atypical hyperplasia and low grade carcinoma will continue to plague our
literature and our profession (15-17).
Given the formidable methodologic problems itemized above, one nihilistic view is that this
is the best we can do. Another, perhaps more optimistic view is to search for molecular
correlates of cancer and precancer to inform and improve on our standard histologic
assessment. However, before we throw up our hands in defeat or rush to blindly embrace the
molecules, it is important to remember that it may not always be necessary to render a finely
tuned definitive diagnosis for this problematic set of lesions. In any given patient, it may be
enough to give a best estimate of risk so that the treating physician and patient can make an
informed decision to pursue a trial of hormonal therapy or proceed to a more definitive
diagnostic (and therapeutic) procedure. In order to develop a more effective, real-world
patient management program, further attempts to develop refined, evidence-based, and
consensus-driven diagnostic criteria for these endometrial risk lesions should address these
methodologic problems in well-designed, systematic, large-scale and independently
confirmed studies.
Selected References
1. Baak JP, Mutter GL, Robboy S, et al. The molecular genetics and morphomety based
endometrial ntraepithelial neoplasia classification system predicts disease progression in
endometrial hyperplasia more accurately than the 1994 World Health Organizaton
classification system. Cancer 2005;103:2304-2312.
2. Hecht JL, Ince TA, Baak JP, et al. Prediction of endometrial carcinoma by subjective
endometrial intraepithelial neoplasia diagnosis. Mod Pathol 2005:18:324-330.
3. Henrickson MR, Longacre TA, Kempson RL. The uterine corpus. In: Mills SE, ed.
Sternberg's Diagnostic Surgical Pathology. New York: Lippincott Williams and Wilkins, 2004.
4. Huang S, Amparo E, Fu Y. Endometrial hyperplasia: histologic classification and
behavior. Surg Pathol 1988;1:215–229.
5
5. Kaku T, Yoshikawa H, Tsuda H, et al. Conservative therapy for adenocarcinoma and
atypical endometrial hyperplasia of the endometrium in young women: central pathologic
review and treatment outcome. Cancer Lett 2001;167:39–48.
6. Kendall BS, Ronnett BM, Isacson C, et al. Reproducibility of the diagnosis of
endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma. Am J Surg
Pathol 1998;22:1012–1019.
7. Kurman R, Kaminski P, Norris H. The behavior of endometrial hyperplasia: a long-term
study of "untreated" hyperplasia in 170 patients. Cancer 1985;56:403–412.
8. Kurman R, Norris H. Evaluation of criteria for distinguishing atypical endometrial
hyperplasia from well-differentiated carcinoma. Cancer 1982;49:2547–2559.
9. Longacre TA, Chung MH, Jensen DN, et al. Proposed criteria for the diagnosis of
well-differentiated endometrial carcinoma: a diagnostic test for myoinvasion. Am J Surg
Pathol 1995;19:371–406
10. Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early
endometrial cancer. Am J Obstet Gynecol 2002;186:651–657.
11. Mutter GL. Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The
Endometrial Collaborative Group. Gynecol Oncol 2000;76:287–290.
12. Mutter GL, Baak JP, Crum CP, et al. Endometrial precancer diagnosis by
histopathology, clonal analysis, and computerized morphometry. J Pathol 2000;190:462–
469.
13. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and
well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol
1997;90:434–440.
14. Skov BG, Broholm H, Engel U, et al. Comparison of the reproducibility of the WHO
classifications of 1975 and 1994 of endometrial hyperplasia. Int J Gynecol Pathol
1997;16:33–37.
15. Soslow RA. Problems with the current diagnostic approach to complex atypical
endometrial hyperplasia. Cancer 2006;106:729-731.
16. Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women
with a biopsy diagnosis of atypical endoemtrila hyperplasia: a Gynecologic Oncology
Group Study. Cancer 2006;106:812-819.
17. Zaino RJ, Kauderer J, Trimble CL, et al. Reproducibility of the diagnosis of atypical
endometrial hyperplasia: a Gynecologic Oncology Group Study. Cancer 2006;106:804811.
6
7
INTERNATIONAL SOCIETY OF GYNECOLOGICAL PATHOLOGISTS
Sunday, March 2, 2008 – 1:30 p.m., Hyatt Regency Hotel, Denver, CO
PATHOLOGY OF THE UTERINE CORPUS, PART 1:
ENDOMETRIUM – CURRENT STATE OF THE ART
ENDOMETRIAL CARCINOMA: CLASSIFICATION AND GENERAL FEATURES
Jaime Prat, M.D., Ph.D., FRCPath.
Hospital de la Santa Creu i Sant Pau
Autonomous University of Barcelona, Spain
For the last two decades, endometrial carcinoma has been subdivided into two major types (types I and
II) based on epidemiology, conventional histopathology, and clinical behavior. Type I, which
comprises approximately 80% of endometrial carcinomas newly diagnosed in the Western world,
occurs predominantly in pre- and peri-menopausal women under unopposed estrogenic stimulation.
These tumors are endometrioid carcinomas (EECs) that morphologically resemble normal
endometrium and are frequently preceded by endometrial hyperplasia. They are usually confined to the
uterus, exhibit low histological grade, and most patients are cured by hysterectomy. In contrast, type II
endometrial carcinomas develop mainly in older post-menopausal women in whom the non-neoplastic
endometrium is atrophic. These tumors are non-endometrioid carcinomas (NEECs), predominantly
high grade serous or clear cell carcinomas, which are not associated with estrogen effect and are
thought to derive from a malignant lesion designated ‘intraepithelial carcinoma’. Frequently, NEECs
invade deeply into the myometrium and follow an aggressive clinical course. Also, it has been found
that the genetic alterations carried by EECs differ from those of NEECs. Most were selected by
analogy with colon cancer and were confirmed afterwards to occur in endometrial carcinoma.
Recently, gene expression profiling has further expanded our knowledge of early genetic events and
reinforced the clinicopathological subgroups originally defined by morphological and clinical features.
However, even if a dualistic model may apply to typical cases, there is often overlap in the clinical,
histopathological, immunohistochemical, and genetic characteristics of the tumors. Most endometrial
carcinomas that are found in an atrophic endometrium are EECs, with a prognosis intermediate
between the two types described above. Furthermore, it has been shown that some NEECs may
develop from preexisting EECs as a result of tumor progression and, in such cases, the tumors may
share histological and molecular features.
Women with an inherited predisposition for endometrial neoplasia tend to develop the disease 10 years
earlier than the general population and have a favorable prognosis. Most of these patients have
hereditary non-polyposis colorectal carcinoma (HNPCC), an autosomal dominant disorder due to
germline mutations in one of the DNA mismatch repair (MMR) genes. Although colorectal cancer
predominates, endometrial carcinoma occurs in 30–60% of cases.
References
1. Bockman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983; 15: 10–7.
2. Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet 2005; 366: 491–505.
3. American Cancer Society. Cancer Facts and Figures 2006. Atlanta: American Cancer Society, 2006.
http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf (accessed Nov 2006).
1
4. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–30.
5. Lax SF. Molecular genetic pathways in various types of endometrial carcinoma: from a
phenotypical to a molecular-based classification. Virchows Arch 2004; 444: 213–23.
6. Catasu´ s Ll, Machin P, Matias-Guiu X, et al. Microsatellite instability in endometrial carcinomas
clinicopathologic correlations in a series of 42 cases. Hum Pathol 1998; 29: 1160–4.
7. Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet
1999; 36: 801–18.
8. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutations carriers of DNA-mismatch-repair
genes. Int J Cancer 1999; 81: 214–8.
2
MADRID SEAP-07 - ADCA DE
ENDOMETRIO: CLASIFICACIÓN
12/02/2008
ENDOMETRIAL CARCINOMA:
CLASSIFICATION AND GENERAL
FEATURES
Jaime Prat, M.D., Ph.D., FRCPath.
Hospital de la Santa Creu i Sant Pau
Autonomous University of Barcelona, Spain
Endometrial Carcinoma
• Most common FGT cancer in western world
• 4th most common cancer in women (6%)
• Only 2% of cancer deaths in women
• Postmenopause (75%)
The two types of Endometrial Carcinoma
Type I
Type II
Age
Pre- and Perimenopausal
Postmenopausal
Unopposed Estrogen
Present
Absent
Hyperplasia-Precursor
Present
Absent
Grade
Low
High
Myometrial Invasion
Minimal
Deep
Histologic Type
Endometrioid
Nonendometrioid
Behavior
Stable
Progressive
Genetic alterations
Microsat Instability
P53 mutations, LOH
Type I
PTEN, Beta-catenin
Modif from Bokhman JV. Gynecol Oncol 1983
Type II
Endometrial Carcinoma
Endometrioid
ER
p53
Non-Endometrioid
Catasús Ll. et al.
Hum Pathol 1998
1
MADRID SEAP-07 - ADCA DE
ENDOMETRIO: CLASIFICACIÓN
12/02/2008
P53
Serous Ca
Endometrioid Ca
Endometrioid Ca
Serous Ca
BAX
TGFβ-RII
IGF-IIR
MSH3
MSH6
MI, PTEN
β-catenin
Endometrioid Ca
NE
High grade
endometrioid Ca
Non-endometrioid Ca
LOH
P53
P53
Catasús Ll, et al.
Hum Pathol 1998
2
INTERNATIONAL SOCIETY OF GYNECOLOGICAL PATHOLOGISTS
Sunday, March 2, 2008 – 1:30 p.m.
Hyatt Regency Hotel, Denver, CO
PATHOLOGY OF THE UTERINE CORPUS, PART 1:
ENDOMETRIUM – CURRENT STATE OF THE ART
MOLECULAR BIOLOGY OF ENDOMETRIAL CARCINOMA
Xavier Matias-Guiu MD,
Department of Pathology and Molecular Genetics.
Hospital Universitari Arnau de Vilanova
University of Lleida, Spain.
The molecular alterations involved in the development of endometrioid carcinomas (EEC) (type I) differ from
those of non-endometrioid carcinomas (NEEC) (type II). Whereas EECs usually show microsatellite instability
(MI), and mutations in the PTEN, k-RAS, PIK3CA, and beta-catenin genes, NEECs exhibit alterations of p53,
loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, Ecadherin and C-erb B2).
Microsatellite instability (MI) was initially noted in cancers of patients with the hereditary non-polyposis colon
cancer (HNPCC), but also in some sporadic colon cancers. EC is the second most common tumor found in
HNPCC patients. MI has been demonstrated in 75% of EC associated with HNPCC, but also in 25-30% of
sporadic EC. EC patients from HNPCC kindreds have an inherited germline mutation in either MLH-1, MSH-2,
MSH-6 or PMS-2 (“first hit”); but EC develops only after the instauration of a deletion or mutation in the
contralateral MLH-1,MSH-2, MSH-6 or PMS-2 allele (“second hit”) in endometrial cells. Once the two hits
occur, the deficient mismatch repair role of the gene (MLH-1,MSH-2, MSH-6 or PMS-2) causes the acquisition
of MI, and the development of the tumor. In sporadic EC, MI occurs more frequently in EEC (30%) than in
NEEC. In sporadic tumors, MLH-1 inactivation by promoter hypermethylation is the main cause of mismatch
repair deficiency. Abnormal methylation of MLH-1 may also be detected in atypical hyperplasias, suggesting
that hypermethylation of MLH-1 may be an early event in the pathogenesis of EEC, preceding the development
of MI. There are controversial data regarding the prognostic significance of MI, but there are some convincing
evidence suggesting association with favourable outcome.
The instauration of MI, the so-called mutator phenotype, in one cell has important molecular implications. The
MI-associated mismatch repair deficiency leads to the accumulation of myriads of mutations in coding and noncoding DNA sequences. Short-tandem repeats, like microsatellites, are particularly susceptible to mismatch
repair alterations, but they are predominantly located in non-coding DNA sequences; and the presence of subtle
mutations (insertions or deletions) do not have consequences in the production of abnormal proteins. However,
some small short-tandem repeats, like mononucleotide repeats, are sometimes located within the coding sequence
of some important genes; (BAX, IGFIIR, hMSH3, and hMSH6 MBD4, CHK-1, Caspase-5, ATR, ATM, BML,
RAD-50, BCL-10, Apaf-1) and they may be potential targets in the process of tumor progression of MI+, EC.
Mutations in these tracts are interpreted as secondary events in the mutator phenotype pathway in cancers with
MI, and usually alter the open reading frame of these genes, giving rise to abnormal or truncated proteins with
altered functions.
The tumor suppressor gene termed PTEN, located on chromosome 10q23.3, is frequently abnormal in
endometrial carcinomas. LOH at chromosome 10q23 occurs in 40% of EC. Somatic PTEN mutations are also
common in EC, and they are almost exclusively restricted to EEC, occurring in 37-61% of them. Interestingly,
several groups have found a concordance between MI status and PTEN mutations; the mutations occur in 6086% of MI positive EEC, but in only 24-35% of the MI negative tumors. Such results have lead to the
speculation that PTEN could be a likely candidate to be target for mutations in the MI positive EC. PTEN
mutations have been detected in endometrial hyperplasias with and without atypia (19% and 21% respectively),
both of them currently regarded as precursor lesions of EEC. Moreover, identical PTEN mutations have been
detected in hyperplasias coexisting with MI positive EEC which suggests that PTEN mutations are early events
in the development of EEC. There are controversial data regarding the prognostic significance of PTEN
mutations in EC, but there are some results that suggest association with favourable prognostic factors.
In agreement with Knudson’s two-hit proposal, LOH at 10q23 frequently coexists with somatic PTEN mutations.
The coexistence of both alterations leads to activation of the PI3K/AKT pathway, which plays a key role in the
regulation of cellular homeostasis. Activated AKT modulates the expression of several genes involved in
suppression of apoptosis and cell cycle progression. However, it has been seen that these two do not necessarily
coexist in the same tumors, challenging the two hit hypothesis for PTEN in EC. In a recent study of our group,
we have detected any of these two genetic alterations in 57.7% of the tumors, but the coexistence of two genetic
alterations (mutation and LOH or double mutations) was seen in only one third of the cases. In such study, the
tumors that exhibited only one of these two alterations (mutation and LOH) were interpreted as having
monoallelic inactivation of PTEN. Interestingly, the tumors with monoallelic inactivation of PTEN presented
frequently mutations in the PIK3CA gene, which codes for the p110α catalytic subunit of PI3K. That means that
the PI3K/AKT pathway can be altered by three different ways; 1) a tumor suppressor gene, such as PTEN, by
showing somatic mutations and LOH, and 2) an oncogene, such as PI3KCA, by activating mutations, and 3) a
single alteration in PTEN coexisting with an activating mutation in PI3KCA.
Mutations in PIK3CA have been described in various tumors and may contribute to the alteration of the
PI3K/AKT signalling pathway in endometrial carcinoma. PI3K is a heterodimeric enzyme consisting of a
catalytic subunit (p110) and a regulatory subunit (p85).The PIK3CA gene, located on chromosome 3q26.32,
codes for the p110α catalytic subunit of PI3K. A high frequency of mutations in the PIK3CA gene has been
reported recently in several types of human cancer, including those of the colon, breast, ovary and stomach. The
mutations are predominantly located in the helical (exon 9) and kinase (exon 20) domains. Oda et al described
mutations in PIK3CA gene in endometrial carcinomas for the first time. In this series, PIK3CA mutations
occurred in 36% of the cases, and coexisted frequently with PTEN mutations. Subsequent studies have shown
that PIK3CA mutations are really frequent in EEC, in association with invasion, and adverse prognostic factors
such as blood vessel invasion. These results suggest that PIK3CA mutations may contribute to activation of the
PI3K/AKT pathway in endometrial carcinomas.
The RAS-RAF-MEK-ERK signalling pathway plays an important role in tumorigenesis. Mutations in the RAS
oncogene have been detected in many different types of tumors. The RAS superfamily of small GTP-binding
proteins has a fundamental role in cell growth and differentiation, transcriptional regulation and apoptosis. The
frequency of k-RAS mutations in EC ranges between 10 to 30%. In some series, K-RAS mutations have been
reported to be more frequent in EEC showing microsatellite instability. In these tumors, K-RAS mutations are
typically transitions, which may be preceded by abnormal DNA methylation. The fact that in EEC, microsatellite
instability frequently coexists with K-RAS methylation-related transitions has lead to the suggestion that these
two alterations are close related. During tumorigenesis, activated RAS is usually associated with enhanced
proliferation, transformation and cell survival. BRAF, another member of the RAS-RAF-MEK-ERK pathways
is very infrequently mutated in EC. RAS effectors like RASSF1A are supposed to have an inhibitory growth
signal, which needs to be inactivated during tumorigenesis. Contradictory results between RASSF1A
inactivation and K-RAS mutation have been obtained in different types of tumors. They were mutually exclusive
events in colorectal and pancreatic cancer, but the correlation was not significant in lung cancer. Recent studies
from our group have demonstrated that RASSF1A inactivation by promoter hypermethylation may contribute
significantly to increased activity of the RAS-RAF-MEK-ERK signalling pathway.
The beta-catenin gene (CTNNB1) maps to 3p21. Beta-catenin appears to be important in the functional
activities of both APC and E-cadherin. Beta-catenin is a component of the E-cadherin-catenin unit, very
important for cell differentiation, and maintenance of the normal tissue architecture. Beta-catenin is also
important in signal transduction. Increased cytoplasmic and nuclear levels of beta-catenin produce
transcriptional activation through the LEF/Tcf pathway. The APC protein down regulates beta-catenin levels
by cooperating with the glycogen synthase kinase 3 beta (GSK-3beta), inducing phosphorylation of the
serine-threonine residues coded in exon 3 of the beta catenin gene (CTNNB 1), and its degradation through
the ubiquitin-proteasome pathway. Mutations in exon 3 of beta-catenin result in stabilization of the protein,
cytoplasmic and nuclear accumulation, and participation in signal transduction and transcriptional activation
through the formation of complexes with DNA binding proteins.Mutations in exon 3 of CTNNB1 with
nuclear accumulation of beta-catenin occur in 14% to 44% of EC. They appear to be independent of the
presence of MI, and the mutational status of PTEN and k-RAS. In all cases, the mutations were
2
homogeneously distributed in different areas of the tumors, which suggest that they do play a role in early
steps of endometrial tumorigenesis. In fact, alterations in beta-catenin have been described in endometrial
hyperplasias that contain squamous metaplasia (morules). Although, there was a good correlation between
CTNNB 1 mutations and beta-catenin nuclear immunostaining, the presence of a cytoplasmic and nuclear
beta-catenin immunoreactivity in some ECs that did not show a mutation in CTNNB suggests that
alterations in other genes of the Wnt/beta-catenin/ LEF-1 pathway may be responsible for the stabilization
and putative transcription activator role of beta-catenin in these tumors. There are controversial data
regarding the prognostic significance of beta-catenin mutations in EC, but they probably occur is tumors with
good prognosis.
Apoptosis is a key process in the regulation of cellular homeostasis. Deregulation of apoptosis plays an important
role in development and progression of cancer. The lack of response to such stimuli can originate a survival
advantage, and the expansion of a population of neoplastic cells. Moreover, cells resistant to apoptosis are likely
to escape the immune surveillance, but they may be also resistant to therapy. Apoptosis-resistant cells may
expand while the patients receive anticancer treatment, and be responsible for relapse. Apoptosis can be initiated
by two main mechanisms: the intrinsic pathway, which has its origin in the mitochondria, and the extrinsic
apoptotic pathway, triggered by the activation of death receptors situated in the cell surface. A final common
feature for execution of the apoptotic programme is the activation of a cascade of caspases, which are proteases
that have a cysteine containing active site that cleaves protein substrates at specific amino acid motifs containing
an aspartic acid residue.
The ‘extrinsic pathway’, is activated by ligand-bound death receptors such as tumor necrosis factor (TNF), Fas or
TRAIL receptors. After ligand binding, the activated death receptors recruit an adaptor protein named Fas
Associated Death Domain (FADD). FADD consists of two protein interaction domains: a death domain (DD)
and a death effector domain (DED). FADD binds to the receptor through interactions between DDs and to procaspase-8 through DED interactions to form a complex at the receptor called the Death Inducing Signalling
Complex (DISC). Recruitment of caspase- 8 through FADD leads to its auto-cleavage and activation. Active
caspase-8 in turn activates effector caspases such as caspase-3 causing the cell to undergo apoptosis by digesting
upwards of a hundred or so proteins. One of the key regulators of this signalling is c-FLIP, which shares a high
degree of homology with caspase- 8 but lacks protease activity. Thus it functions by competing with caspase-8
for binding to the DISC. In some type of cells this relatively simple pathway is enough to trigger apoptosis, but in
other types of cells, the death receptor apoptotic pathway requires mitochondrial amplification. The BH3-only
protein Bid is cleaved by caspase-8 and is then translocated to the mitochondria to activate the intrinsic pathway,
thus connecting the two caspase activation pathways and amplifying the death receptor apoptotic signal. Thus,
alterations in the mitochondrial pathway may affect the ability to induce apoptosis by death receptors.
There are many evidences suggesting that alteration of apoptosis is important in development and progression of
EC. Several of the molecular abnormalities that have been detected in EC may be associated with apoptosis
deregulation. EEC show a high frequency of mutations in PTEN, which lead to constitutively active Akt, which
in turn suppresses apoptosis triggered by various stimuli. Moreover, the recent evidence that NF-kB activation is
frequent in endometrial carcinoma may explain the presence of apoptosis resistance by activation of target genes
such as FLIP and Bcl-XL. p53 alterations, which are characteristic of NEEC, may also occur in endometrioid
tumors, particularly in those neoplasms showing overlapping features between types I and II tumors; and they
may have an impact in apoptosis at several different levels. Also, members of the Bcl-2 family of genes are
abnormal in endometrial carcinoma. For example, BAX is a target gene for mutations in EEC with microsatellite
instability, and may have a role in resistance to apoptosis in these tumors. Finally, several other proteins involved
in apoptotic control (survivin) have also been shown to be abnormal in endometrial carcinoma.
An important protein responsible for apoptosis resistance in endometrial carcinoma is FLIP. FLIP expression is
frequent in endometrial carcinomas. A direct evidence of the role of FLIP in TRAIL apoptosis resistance on
endometrial carcinoma cells is provided by treatment with specific siRNA targeting FLIP. Transfection of
endometrial carcinoma cell lines with FLIP siRNA results in a marked decrease in cell viability after TRAIL
exposition. This is accompanied by activation of both caspase-8 and caspase-3 suggesting activation of the
extrinsic pathway. Recent studies have shown that FLIP may be regulated by a cellular complex composed by
CK2-BRAF-KSR1. This is interesting because that will connect apoptosis resistance with the RAS-RAF-MEKERK signalling pathway.
3
In contrast to EEC, NEEC show p53 mutations (90%), inactivation of p16 (40%) and E-cadherin (80-90%), cerbB2 amplification (30%), alterations in genes involved in the regulation of the mitotic spindle checkpoint
(STK-15) and loss of heterozygosity at multiple loci, reflecting the presence of chromosomal instability. While
p53 mutations occur in 90% of NEEC, they are only present in 10-20% of EEC, which are mostly grade 3
tumors. The p53 protein can induce apoptosis or prevent a cell from dividing if there is DNA damage. Mutation
of the p53 gene diminishes the cell’s ability to repair damage to DNA before entry to S-phase, leading to a
greater chance that mutations will be fixed in the genome and passed to successive generations of cells.
Inactivation of the cell cycle regulator p16 is also more frequent in NEEC (40%) than in EEC (10%). The
underlying mechanism is not clear, but probably involves deletion and promoter hypermethylation. Reduced
expression of E-cadherin is frequent in EC, and may be caused by LOH or promoter hypermethylation. In fact,
LOH at 16q22.1 is seen in almost 60% of NEEC, but only in 22% of EEC. C-erbB2 overexpression and
amplification are also seen more frequently in NEEC (43% and 29%) than in EEC. However, the most typical
molecular feature of NEEC is chromosomal instability. This phenomenon is characterized by the presence of
widespread chromosomal gains and losses, which reflect the presence of aneuploidy. cDNA arrays have
demonstrated that NEEC usually show up-regulation of genes (STK-15, BUB1, CCNB2) that are involved in the
regulation of the mitotic spindle checkpoint. One of them, STK-15, which is essential for chromosome
segregation and centrosome functions, is frequently amplified in NEEC.
None of the five main alterations of EEC (MI, and mutations in PTEN, k-RAS, PIK3CA and b-catenin) plays a
significant role in NEEC. However, the occasional detection of these molecular alterations in NEEC, show that
NEEC might develop by following two different pathways: 1) de novo, through p53 mutations, LOH at several
loci, and some other, still unknown, gene alterations; or 2) dedifferentiation from pre-existing EEC. This
hypothesis would explain the existence of mixed EEC-NEEC, and the presence of MI, as well as alterations in
PTEN, K-RAS or beta-catenin in NEEC. According to this point of view, de novo NEEC (by far the most
common situation) would fullfill the clinicopathologic and molecular features of NEEC (pure papillary serous or
clear cell type morphology, old age, absence of estrogen stimulation, lack of prexisting endometrial hyperplasia,
p53 mutations, lack of MI or PTEN mutations), whereas dedifferentiated NEEC, would exhibit overlapping
features with EEC (mixed NEEC-EEC morphology, early age of presentation, evidence of estrogen stimulation
or pre-existing hiperplasia, coexistence of p53 mutations and MI or PTEN mutations).
cDNA array studies have demonstrated that the expression profiling of EEC is different from that of NEEC. In
one study, 191 genes exhibited a >2-fold differences between 10 EECs and 16 NEECs. One of the genes, TFF3
was significantly up-regulated in EECs, while increased expression of FOLR was seen in NEECs. In a different
study, a different expression profile was seen between EEC and NEEC, and the differences involved 66 genes.
Interestingly, estrogen-regulated genes were up-regulated in EEC, whereas NEEC showed increased expression
of genes involved in the regulation of the mitotic spindle checkpoint. A third study demonstrated differentially
expression of 1,055 genes between EECs and serous carcinomas. Genes up-regulated in serous carcinomas were
IGF2, PTGS1 and p16, while genes up-regulated in EEC included TFF3, FOXA2 and MSX2. A different study
identified 315 genes that statistically differentiated EEC from NEEC. Moreover, a different expression profile
was also found between EC associated with microsatellite instability and stable EC. Interestingly, two members
of the secreted frizzled related protein family (SFRP1 and SFRP4) were more frequently down-regulated in EC
with microsatellite instability. In a different study, it was seen that the tumors (ovarian and uterine) with beta
catenin alterations, showed common gene expression profile. A group of investigators have also identified, by cDNA array studies, up-regulation of RUNX1/AML1 and ERM/ETV5 in EC, and suggested an implication of
such genes in myometrial invasion. One study compared the expression profiles of similar histological subtypes
of ovarian and endometrial carcinomas; and showed that clear cell carcinomas had a very similar profile,
regardless of the organ of origin. In contrast, differences were seen when comparing endometroid and serous
carcinomas of ovarian and endometrial origin.
REFERENCES
1.
2.
3.
Bockman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983; 15:10-17.
Lax SF, Kurman RJ: A dualistic model for endometrial carcinogenesis based on immunohistochemical and
molecular genetic analyses. Verh Dtsch Ges Path 1997; 81:228-232
Prat J, Gallardo A, Cuatrecasas M, Catasus L. Endometrial carcinoma: Pathology and genetics.
4
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20-
2122
23
24
25
26-
Pathology 2007; 39:72-87
Caduff RF, Johnston CM, Svoboda-Newman SM, Poy EL, Merajver SD, Frank TS: Clinical and
pathological significance of microsatellite instability in sporadic endometrial carcinoma. Am J Pathol 1996;
148:1671-1678
Duggan BD, Felix JC, Muderspach LI, Tourgeman D, Zheng J, Shibata D: Microsatellite instability in
sporadic endometrial carcinoma. J Natl Cancer Inst 1994; 86:1216-1221
Kobayashi K, Sagae S, Kudo H, Koi S, Nakamura Y: Microsatellite instability in endometrial carcinomas:
frequent replication errors in tumors of early onset and/or of poorly differentiated type. Genes Chromosom
Cancer 1995; 14:128-132
Risinger JI, Berchuck A, Kohler MF, Watson P, Lynch HT, Boyd J: Genetic instability of microsatellites in
endometrial carcinoma. Cancer Res 1993; 53:5100-5103.
Catasús Ll, Machin P, Matias-Guiu X, Prat J. Microsatellite instability in endometrial carcinomas
clinicopathologic correlations in a series of 42 cases. Human Pathol. 1998; 29:1160-1164.
Gurin ChC, Federici MG, Kang L, Boyd J: Causes and consequences of microsatellite instability in
endometrial carcinoma. Cancer Res 1999; 59:462-466.
Sakamoto T, Murase T, Urushibata H et al: Microsatellite instability and somatic mutations in endometrial
carcinomas. Gynecol Oncol 1998; 71:53-58.
Basil JB, Goodfellow PJ, Rader JS, Mutch DG, Herzog TJ. Clinical significance of microsatellite instability
in endometrial carcinoma. Cancer 2000; 89:1758-1764.
Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S. Tumor
microsatellite instability and clinical aoutcome in young patients with colorectal cancer. N Engl J Med
2000; 342:69-77.
Catasus Ll, Matias-Guiu X, Machin P, Muñoz J, Prat J: BAX somatic framshift mutations in endometrioid
adenocarcinomas of the endometrium: evidence for a tumor progression role in endometrioid carcinomas
with microsatellite instability. Lab Invest 1998; 78:1439-1444.
Catasus Ll, Matias-Guiu X, Machin P, Zannoni GF, Scambia G, Benedetti Panici PL, Prat J: Frameshift
mutations at coding mononucleotide repeat microsatellites in endometrial carcinomas with microsatellite
instability. Cancer 2000; 88:2290-2297.
Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG. MLH1 promoter hypermethylation is
associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene
1998; 17:2413-2417.
Esteller M, Catasus Ll, Matias-Guiu X, Mutter GL, Prat J, Baylin SB, Herman JG: hMLH1 promoter
hypermethylation is an early event in human endometrial tumorigenesis. Am J Pathol 1999; 155:17671772.
Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JPA Lees, Weng LP, Eng Ch. Altered PTEN expression
as a Diagnostic Marker for the Earliest Endometrial Precancers. J Natl Cancer Inst 2000;92:924-31.
Terakawa N., Kanamori Y., Yoshida S. Loss of PTEN expression followed by Akt phosphorylation is a
poor prognostic factor for patients with endometrial cancer. Endocr Relat Cancer 2003;10:203-8.
Salvesen Hb., Stefansson I., Kalvenes MB., Das S., Akslen LA. Loss of PTEN expression is associated with
metastatic disease in patients with endometrial carcinoma. Cancer 2002;94:2185-91.
Kanamori Y., Kigawa J., Itamochi H., Sultana H., Suzuki M., Ohwada M., Kamura T., Sugiyama T.,
Kikuchi Y., Kita Y., Fujiwara K., Terakawa N. PTEN expression is associated with prognosis for patients
with advanced endometrial carcinoma undergoing postoperative chemotherapy. Int J Cancer 2002;100:6869.
Bussaglia E, del Rio E, Matias-Guiu X, Prat J. PTEN mutations in endometrial carcinomas. A molecular
and clinicopathologic analysis of 38 cases. Hum Pathol 2000;31:312-317.
Tashiro H, Blazes MS, Wu R et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in
other common gynecological malignancies. Cancer Res 1997;57:3935-3940.
Kong D, Suzuki A, Zou TT et al. PTEN1 is frequently mutated in primary endometrial carcinomas. Nat
Genet 1997;17:143-144.
Risinger JI, Hayes AK, Berchuck A, Barrett JC. PTEN/MMAC1 mutations in endometrial cancers. Cancer
Res 1997;57:4736-4738.
Levine RL, Cargile CB, Blazes MS, van Rees B, Kurman RJ, Hedrick Ellenson L. PTEN mutations and
microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid
carcinoma. Cancer Res 1998;58:3254-3258.
Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and
5
PTEN genes in endometrial carcinoma. Cancer Res. 2005 65:10669-73.
27- Velasco A, Bussaglia E, Pallares J, Dolcet X, Llobet D, Encinas M, Llecha N, Palacios J, Prat J, MatiasGuiu X.PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS
alterations.Hum Pathol. 2006 37:1465-72.
28- Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, Ellenson LH.PIK3CA and
PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia.Clin Cancer Res.
2006;12:5932-5.
29- Catasus L, Gallardo A, Cuatrecasas M, Prat J.PIK3CA mutations in the kinase domain (exon 20) of uterine
endometrial adenocarcinomas are associated with adverse prognostic parameters.Mod Pathol. 2008 (in
press)
30. Swisher EM, Peiffer-Scheider S, Mutch DG, Herzog TJ, Rader JS, Elbendary A, Goodfellow PJ:
Differences in patterns of TP53 and KRAS2 mutations in a large series of endometrial carcinomas with or
without microsatellite instability. Cancer 1999; 85:119-126.
31. Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L. The frequency of p53, K-ras mutations, and
microsatellite instability in endometrioid and serous carcinoma: evidence of distinct molecular gen. Cancer
2000; 88:814-824.
32. Lagarda H, Catasus Ll, Argüelles R, Matias-Guiu X, Prat, J. K-ras mutations in endometrial carcinoma with
microsatellite instabilit. J Pathol 2001; 193:193-199.
33. Fukuchi T, Sakamoto M, Tsuda et al: Beta-catenin mutations in carcinoma of the uterine endometrium.
Cancer Res 58:3526-3528, 1998.
34. Kobayashi K, Sagae S, Nishioka Y et al: Mutations of the beta-catenin gene in endometrial carcinomas. Jpn
J Cancer Res 90:55-59, 1999.
35. Mirabelli-Primdahl L, Gryfe R, Kim H et al: beta-catenin mutations are specific for colorectal carcinomas
with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer
Res 59:3346-3351, 1999.
36. Schlosshauer PW, Pirog EC, Levine RL, Hedrick-Ellenson L: Mutational analysis of the CTNNB1 and
APC genes in uterine endometrioid carcinoma. Mod Pathol 13:1066-1071, 2000.
37 Machin P, Catasus L, Pons C, Muñoz J, Matias-Guiu X, Prat J:CTNNB1 mutations and beta-catenin
expression in endometrial carcinomas.Human Pathol 2002 33:206-212
38 Moreno-Bueno G, Hardisson D, Sánchez C, Sarrió D, Cassia R, García-Rostán G, Prat J, Guo M, Herman
JG, Matías-Guiu X, Esteller M, Palacios J.Abnormalities of the APC/beta-catenin pathway in endometrial
cancer.Oncogene. 2002 14; 21:7981-90.
39 Pallares J, Martinez-Guitarte JL, Dolcet X, Llobet D, Rue M, Palacios J, Prat J, Matias-Guiu X:
Abnormalities in NF-kB family and related proteins in endometrial carcinoma. A tissue microarray study. J
Pathol 2004 13:569-577
40. Dolcet X, Llobet D, Pallares J, Rue M, Comella JX, Matias-Guiu X.FLIP is frequently expressed in
endometrial carcinoma and has a role in resistance to TRAIL-induced apoptosis.Lab Invest. 2005 85:88594.
41. Pallares J, Martínez-Guitarte JL, Dolcet X, Llobet D, Rue M, Palacios J, Prat J, Matias-Guiu X.Survivin
expression in endometrial carcinoma: a tissue microarray study with correlation with PTEN and STAT-3.
Int J Gynecol Pathol. 2005 24:247-53
43. Llobet D, Eritja N, Encinas M, Llecha N, Yeramian A, Pallares J, Sorolla A, Gonzalez-Tallada FJ, MatiasGuiu X, Dolcet X.CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial
carcinoma cells. Oncogene. 2008 (in press)
44. Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L: p53 gene mutations are common in
uterine serous carcinoma and occurs early in their pathogenesis. Am J Pathol 1997; 150:177-185
45- Sherman ME, Bur ME, Kurman RJ: p53 in endometrial cancer and its putative precursors: Evidence for
diverse pathways of tumorigenesis. Human Pathol 1995; 26:1268-1274.
46- Egan JA, Ionescu MC, Eapen E, Jones JG, Marshall DS. Differential expression of WT1 and p53 in serous
and endometrioid carcinomas of the endometrium. Int J Gynecol Pathol. 2004 23:119-22.
47- Alkushi A, Lim P, Coldman A, Huntsman D, Miller D, Gilks CB. Interpretation of p53 immunoreactivity in
endometrial carcinoma: establishing a clinically relevant cut-off level. Int J Gynecol Pathol. 2004 23:12937.
48- Moreno-Bueno G, Hardisson D, Sarrió D, Sánchez C, Cassia R, Prat J, Herman JG, Esteller M, Matías-Guiu
X, Palacios J.Abnormalities of E- and P-cadherin and catenin (beta-, gamma-catenin, and p120ctn)
expression in endometrial cancer and endometrial atypical hyperplasia.J Pathol. 2003 1999:471-8
6
49- Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L, Maxwell GL, Fowler JM. HER-2
is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of
surgically staged patients. J Clin Oncol. 2006 ;24:2376-85
50- Tritz D, Pieretti M, Turner S, Powell D: Loss of heterozygosity in usual and special variant carcinomas of
the endometrium, Hum Pathol 1997, 28:607-612
51- Moreno-Bueno G, Sánchez-Estévez C, Cassia R, Rodríguez-Perales S, Díaz-Uriarte R, Domínguez O,
Hardisson D, Andujar M, Prat J, Matias-Guiu X, Cigudosa JC, Palacios J.Differential gene expression
profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed
and amplified in nonendometrioid carcinomas.Cancer Res. 2003 63:5697-702.
52- Risinger JI, Maxwell GL, Chandramouli GV, Jazaeri A, Aprelikova O, Patterson T, Berchuck A, Barrett
JC.Microarray analysis reveals distinct gene expression profiles among different histologic types of
endometrial cancer.Cancer Res. 2003 63:6-11
53- Maxwell GL, Chandramouli GV, Dainty L, Litzi TJ, Berchuck A, Barrett JC, Risinger JI.Microarray
analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles
associated with different histologic types of uterine cancer. Clin Cancer Res. 2005 11:4056-66.
54- Cao QJ, Belbin T, Socci N, Balan R, Prystowsky MB, Childs G, Jones JG.Distinctive gene expression
profiles by cDNA microarrays in endometrioid and serous carcinomas of the endometrium.Int J Gynecol
Pathol. 2004 23:321-9.
55- Risinger JI, Maxwell GL, Chandramouli GV, Aprelikova O, Litzi T, Umar A, Berchuck A, Barrett JC.Gene
expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates
distinct pathways of aberrant signaling.Cancer Res. 2005 ;65:5031-7
56- Shedden KA, Kshirsagar MP, Schwartz DR, Wu R, Yu H, Misek DE, Hanash S, Katabuchi H, Ellenson
LH, Fearon ER, Cho KR.Histologic type, organ of origin, and Wnt pathway status: effect on gene
expression in ovarian and uterine carcinomas.Clin Cancer Res. 2005 11:2123-31
60- Planagumà J, Díaz-Fuertes M, Gil-Moreno A, Abal M, Monge M, García A, Baró T, Thomson TM,
Xercavins J, Alameda F, Reventós J.A differential gene expression profile reveals overexpression of
RUNX1/AML1 in invasive endometrioid carcinoma.Cancer Res. 2004 64:8846-53
61- Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ, Barrett JC, Boyd J, Birrer
MJ.Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial
cancer.Clin Cancer Res. 2005 11:6422-30
7
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
Endometrioid Carcinoma
Molecular Biology of
Endometrial Carcinoma
Genetic Alterations
PIK3CA
30%
PTEN
30-60%
Microsatellite
Instability
20-30%
X. Matias-Guiu, M.D.
Department of Pathology and Molecular Genetics
Hospital Arnau deVilanova
University of Lleida, Spain
K-ras
10-30%
Beta-catenin
28-35%
Microsatellite Instability
Microsatellite Instability
• Mismatch repair (MMR) genes (MLH1, MSH2)
D5S107 D10S197 D12S79 D12S95 D18S58
N
BAT-25
T N T N T N T N T
• Frameshift mutations in target genes
BAT-26
N
• Hereditary Non-Polyposis Colorectal Cancer
syndrome (Lynch II)
T
• Sporadic cancers: colon, stomach, pancreas,
ovary, and endometrium
T+N
Endometrial Ca
HNPCC (Lynch II)
(n =118)
Microsatellite Instability
MSH2
MLH1
Endometrioid Ca
Non-endometrioid Ca
37/109 (35%)
1/8
(12%)
MSH2
MLH1
(Mutations)n
T
1
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
Active Gene
PRO
MLH1
• Random Methylation Errors
PRO
Reduced Expression
MLH1
Inactivation of DNA Mismatch Repair Genes
by Promoter Hypermethylation
in Endometrial Carcinoma
MSP-hMLH1
E28
U
M
E21
U
M
E39
U
E80
M
U
M
E31
U
E9
M
U
H2O
IVD
M
U
M
U
M
• Clonal Selection of Cells
• Further Random Methylation Errors
PRO
Silenced Gene
MLH1
MI +
8/8 (100%)
MI -
0/14
(0%)
Esteller et al. 1999
Altered
methylation
MLH1
MI
PTEN
BAX
TGF-BetaRII
IGFIIR
MSH3
MSH6
Caspase 5
H
T
D18S58
N
T
p16
U
T
T
H
H
M
U
M
APC
E-Cadherin
Mononucleotide repeat microsatellite
Altered
methylation
MLH1
PTEN
p16
APC
E-Cadherin
MI
BAX
TGF-BetaRII
IGFIIR
MSH3
MSH6
Caspase 5
Genes
BAX
MSH3
MSH6
TGF-BetaRII
IGFIIR
(G)8
(A)8
(C)8
(A)10
(G)8
2
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
Endometrial Ca, MI +
(Frameshift mutations)
BAX
gene
GGGGGGGG
Caspase 5
45.4%
BAX
41%
Bcl-10
27%
APAF-1
27%
MSH3
25%
IGFIIR
12.5%
BLM
13.5%
--------------------------Overall
77%
Pr
gene
GGGGGGG
Pr
gene
GGGGGGGGG
Pr
Catasús Ll. et al.
Cancer 2000; 88:2290-7
BAX (G)8
T1
T1
T2
T2
BAX
T1
T1
T2
N
T
T3
T4
Metastasis
3
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
Hyperplasia
Carcinoma
IGFIIR
CASE 2487
N
T
PTEN
CASE 2483
M
N
T
CASE 2490
M
T
M
Altered
methylation
MLH1
MI
BAX
RIZ
IGFIIR
MSH3
MSH6
Caspase 5
K-ras
Beta-catenin
MMP-7
Cyclin D1
Integrins
Growth factor
receptors
PTEN alterations in the Endometrium
Plasma
Shc
FAK
Ptdins membrane
(3,4,5)P3
PI 3-kinase
Akt /PKB
PTEN
Adhesion
and
migration
• Early event
• PTEN-null glands (1%) in normal proliferative
endometrium (43% of cases)
• PTEN mutations in hyperplasia (15-55%)
• PTEN mutations in carcinoma (30-60%)
Survival
proliferation
and migration
Endometrial Carcinoma
PTEN mutations
PTEN Mutations
ET-28
T
• Endometrioid
• Non-Endometrioid
T
N
963-968 ins A
59/109 (54%)
0/5
(0%)
ET-9
---------------------------------------------------------------
• MI+
ET-31
N
27/59 (46%)
T
N
ET-47
ET-58
T
T
N
N
TTA
GTA
L146V
P=0.005
4
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
Endometrial Hyperplasia
PTEN mutations
T
H1 H2 H3 N
N
H
T
ET- 82
ET-140
5
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
MUTATION
PTEN
Endometrial Carcinoma
IHC
PTEN
LOH
N
PROMOTER HYPERMETHYLATION
T
Alterations
42/78
54%
Mutation
LOH
Methylation
34/78
24/78
6/34
44%
31%
18%
One hit
Two hits
23/78
19/78
29%
24%
PTEN
PTEN
Endometrioid Carcinoma
Biallelic inactivation
Haplo-insufficiency
Genetic Alterations
PIK3CA
30%
PTEN
30-60%
Microsatellite
Instability
20-30%
K-ras
10-30%
Beta-catenin
28-35%
P
ATP
PIP2
Dephosphorylation
PTEN
PI3K
Phosphorylation
High frequency of coexistent
mutations of PIK3CA and PTEN
genes in Endometrial Carcinoma
ADP
PIP3
Oda K, et al
Cancer Res, December 2005
AKT-P
Cell Proliferation and Survival
1
5-Matias-Guiu ISGyP - Denver-08
PIK3CA mutations
PIK3CA
36% (24/66)
PTEN
56% (37/66)
---------------------------------------PIK3CA + PTEN
26% (17/66)
12/02/2008
PTEN alterations
(Correlations in Endometrial Carcinoma)
• PTEN mutations and MI
• ↓ PTEN expression and ↑ phospho-AKT
• ↓ PTEN expression and ↑ Survivin
Oda K, et al
Cancer Res, December 2005
Mutaciones PIK3CA
1
2
3
2
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
CTNNB1 mutation
Endometrial Carcinoma
CTNNB1 mutations
• Endometrioid
15/59
(25.4%)
• Non-Endometrioid
0/14
(0%)
• MI+
• MI-
6/19
9/54
(31.5%)
(16.6%)
Beta-catenin nuclear
accumulation
Machin P et al, Hum Pathol 2002
MMP-7 expression
Cyclin D1 expression
Beta-Catenin Mutations in Endometrial Cancer
CTNNB1
TCT
TGT
S37C
EXON 3
Not associated with Microsat Instability
More frequent in early stages?
Good prognostic marker?
1
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
Genetic alterations in Atypical Endometrial Hyperplasia
PTEN alt, K-RAS, and Beta-Catenin mutations, and MI
n=78
AH (11)
Number of alterations
B-CAT
PTEN
RAS
MSI
1 (9%)
4 (36%)
4 (36%)
1(9%)
0
0
0
AHWSM (14) 7 (50%)
0
27%
1
32%
2
27% (MI+PTEN: 13/19)
3
11% (MI+PTEN+RAS: 6/9)
4
3%
Alterations
Single alterations
PTEN (n=42)
(33%) 14
MI (n=30)
(13%)
4
K-RAS (n=16)
(12%)
2
Beta-catenin (n=14)
(35%)
5
Bratchel, et al.; Am J Surg Pathol 2005
Growth Factors
Death Factors
NF-kappaB family members
Death Receptors
Adapter Protein
Caspase 8
PI3K
FLIP
PTEN
BAX
(p65)
AKT
APAF-1
CYT-C
Caspase 9
c-
BCLxL
NFKB
Caspase 3
Survivin
APOPTOSIS
Adapted from Karin et al., 2004
Stimulus
P
p65
p65
IκB
P
Ub
IκB
p50
p50
p65
p65
p65
Ub
p65
Ub
P
p50
IκB
P
p65
P
p50
IκB
P
Proteosome
p50
p52
1
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
NF-κB
FLIP is frequenly overexpressed in Endometrial Adenocarcinoma
(Endometrial Carcinoma)
•
•
•
•
NF- κB expression is frequent
P50-p65 co-expression (classic form)
Bcl-3/p52 complexes are expressed
Target genes are expressed (Cyclin D1,
Flip, Bcl-xL)
Pallares J et al: J Pathol 2004 204:569-577
CON
siRNA
FLIP
Dolcet X et al: Lab Invest 2005 85:885-894
siRNA
IK
KLE
Downregulation of FLIP by specific siRNA
sensitizes to TRAIL-induced apoptosis
2
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
Growth Factors
Death Factors
NE
Death Receptors
Adapter Protein
Caspase 8
EEC
PI3K
FLIP
Supervised analysis between
normal endometrium and
Endometrioid Endometrial
Carcinoma
PTEN
BAX
AKT
APAF-1
CYT-C
Caspase 9
Hierarchical Clustering
of 92 genes with
differential expression
patterns between
NE and EEC
(p<0.05), using a
threshold of 2-fold
BCLxL
NFKB
Caspase 3
Survivin
APOPTOSIS
CDH1 LOH in Endometrial Carcinoma
E-Cadherin immunostaining in Endometrial Carcinomas
N
16q22.1
D16S3057
D16S265
*
D16S398
CDH1
T
D16S496
D16S752
D16S496
Endometrioid
Serous
Preserved E-cadherin
Reduced E-cadherin
Focal loss of E-cadherin
Reduced E-cadherin
CDH1 LOH (22%)
Endometrioid
41/82 (50.0%)
Non-Endometrioid
27/31 (87.1%)
0.001
CDH1 LOH (57%)
1
5-Matias-Guiu ISGyP - Denver-08
12/02/2008
CYCLIN D1 and CYCLIN E
NEEC
Cyclin D1
CCND1
Cyclin E
EEC
G.Symbol A. Number
Hierarchical Clustering
of 55 genes with
differential expression
between
EEC and NEEC
(Supervised analysis,
p<0.05)
CCNE
Cyclin D1 amplification
FISH
EEC
1/48 (2%)
NEEC
5/19 (26%)
Cyclin E amplification
EEC
1/21 (5%)
NEEC
5/12 (42%)
Up-regulated genes in EEC
Up-regulated genes in NEEC
MGB2
10.4
CCNB2
2.6
LTF
6.5
DEK
2.6
NCOR1
3.9
STK15
2.5
END3
2.4
BUB1
2.5
p=0.033
Mean Fold
Expression
p=0.050
p<0.001
2
1.5
1
0.5
0
BUB1
EEC
NEEC
DEK
STK15
25
22.5
20
17.5
15
12.5
10
7.5
5
2.5
0
NEEC
EEC
Breast cancer
p<0.001
100
80
% Gene
amplification
3
2.5
STK15 amplification in Breast and Gynecological cancer
MGB
NEEC
60
40
Ovary
20
Cervix
Breast
0
TaqMan RT-PCR data validation
Endometrial cancer
Moreno-Bueno et al; Cancer Res 2003
Hyperplasia
BAX
TGFβ-RII
IGF-IIR
MSH3
MSH6
Carcinoma
PTEN
MI, PTEN
β-catenin
Altered
methylation
MLH1
MI
PIK3CA
BAX
RIZ
IGFIIR
MSH3
MSH6
Caspase 5
Non-endometrioid Ca
P53
P53
K-ras
High grade
endometrioid Ca
Endometrioid Ca
NE
Beta-catenin
Chromosome Instability
LOH
Amplification
MMP-7
Cyclin D1
Cadherin E
Cyclin D1
Cyclin E
STK15
1
Objectives
2008 ISGP Symposium
Morphology and prognostic factors
in endometrial adenocarcinoma
Richard J. Zaino, MD
Hershey Medical Center
Penn State University
Hershey, PA
rzaino@psu.edu
1) Review the biology of the major types of
endometrial adenocarcinoma
2) Examine the application of and significance
of the CAP template for endometrial
cancer
3) Examine the utility and limitations of the
FIGO staging scheme for endometrial
cancer
4) Examine prognostic factors in endometrial
carcinoma
MACROSCOPIC
CAP approved
(so it must be good for us)
Surgical Pathology Cancer Case Summary
(Checklist)
Protocol revision date: January 2005
Based on AJCC/UICC TNM, 6th edition and FIGO 2001
Annual Report
ENDOMETRIUM: Hysterectomy, With or
Without Other Organs or Tissues
Specimen Type
___ Hysterectomy
___ Radical hysterectomy (includes parametria)
___ Pelvic exenteration
*Tumor Site
*Specify location(s), if known: _____________________________
Tumor Size
Greatest dimension: ___ cm
*Additional dimensions: ___ x ___ cm
___ Cannot be determined (see Comment)
Other Organs Present (check all that apply)
___ None
___ Right ovary
___ Left ovary
___ Right fallopian tube
___ Left fallopian tube
___ Urinary bladder
___ Vagina
___ Rectum
___ Other(s) (specify): _________________________
1
Significance of maximum size of
endometrial adenocarcinoma
Relative few studies addressing
prognostic significance
Mariani et al, 2001 and 2002
size > 2cm is a predictor of lymphatic
failure and distant failure by univariate
analysis but not by multivariate analysis
MICROSCOPIC
Histologic Type
___ Endometrioid adenocarcinoma, not otherwise characterized
___ Endometrioid adenocarcinoma, secretory (variant)
___ Endometrioid adenocarcinoma, ciliated cell (variant)
___ Endometrioid adenocarcinoma, with squamous metaplasia
___ Adenosquamous carcinoma
___ Serous adenocarcinoma
___ Clear cell adenocarcinoma
___ Mucinous adenocarcinoma
___ Squamous cell carcinoma
___ Mixed carcinoma (specify types and percentages):
________________________
___ Undifferentiated carcinoma
Histologic Grade (if applicable)
(Grading system below applies primarily to endometrioid carcinoma)
___ Not applicable
___ GX: Cannot be assessed
___ G1: 5% or less nonsquamous solid growth
___ G2: 6% to 50% nonsquamous solid growth
___ G3: More than 50% nonsquamous solid growth
Pathologic classification of
endometrial adenocarcinomas
1980
adenocarcinoma
adenoacanthoma
adenosquamous
clear cell
2005
endometrioid
endometrioid w squamous diff
villoglandular
secretory
mucinous
serous (UPSC)
clear cell
mixed
2
Endometrioid adenocarcinoma
Smooth luminal border
Estrogen receptor
Secretory adenocarcinoma
Villoglandular adenocarcinoma
Adenocarcinoma
with squamous differentiation
3
Mucinous adenocarcinoma
Papillary serous carcinoma (UPSC)
Clear cell adenocarcinoma
Carcinoma with clear cells
Carcinoma with clear cells
4
Two types of endometrial
adenocarcinoma (Bokhman, 1981)
Type I
With hyperplasia
(EIN)
Hyperestrinism
Endometrioid
Well differentiated
Steroid receptor +
Good prognosis
PTEN null/MSI
uterine papillary serous carcinoma
Type II
No hyperplasia
(EIC)
No hyperestrinism
Serous/CC
Poorly differentiated
Steroid receptor –/+
Poor prognosis
p53 overexpression
papillae
Gaping glands
Scalloped luminal
border
polyp
Serous carcinoma
Frayed or scalloped luminal border
5
MIB1
p53
ER
Survival in endometrial
adenocarcinoma (all stages)
Tumor type
5 yr survival
Endometrioid
80 – 90%
UPSC
10 – 30%
UPSC – patterns of spread
Author
Carcangiu
Mallipeddi
Lee
Gitsch
Carcangiu
Cirisano
Wheeler
Goff
Sherman
Geisler
sites of disease
intrabdominal/small bowel
nodes, bowel, omentum, cyto
ovaries, nodes, peritoneum
cyto, nodes, omentum, liver, dia
adnexa, peritoneum, omentum, nodes
nodes, ovaries, peritoneum, omentum
ovary, omentum, bowel
ovary, nodes, omentum, peritoneum
nodes, cyto, ovary, omentum
omentum, cyto, peritoneum, nodes
6
MICROSCOPIC
Histologic Type
___
___
___
___
___
___
___
___
___
___
___
Endometrioid adenocarcinoma, not otherwise characterized
Endometrioid adenocarcinoma, secretory (variant)
Endometrioid adenocarcinoma, ciliated cell (variant)
Endometrioid adenocarcinoma, with squamous metaplasia
Adenosquamous carcinoma
Serous adenocarcinoma
Clear cell adenocarcinoma
Mucinous adenocarcinoma
Squamous cell carcinoma
Mixed carcinoma (specify types and percentages): ________________________
Undifferentiated carcinoma
Histologic Grade (if applicable)
(Grading system below applies primarily to endometrioid carcinoma)
___ Not applicable
___ GX: Cannot be assessed
___ G1: 5% or less nonsquamous solid growth
___ G2: 6% to 50% nonsquamous solid growth
___ G3: More than 50% nonsquamous solid growth
Grade 1
Grade 1
Grade 2
7
Grade 2
Grade 3
Grade 3 (nuclei)
Overall grade 2
Grade 3
Grade 1 (architecture)
Grade 3 nuclei
Overall grade 2
8
Stage I adenocarcinoma of the
endometrium (FIGO 2003)
Grade
1
2
3
5 year survival
92%
88%
75%
Grading endometrial adenocarcinoma
Two grades versus three
FIGO – 3 grades, architecture +/- nuclear
GOG – 3 grades, architecture
Hachisuga -3 grades, nuclear (quantitative)
Taylor et al – 2 grades, architecture (10% solid)
Scholten – 2 grades, architecture (50% solid)
Lax – 2 grades, architecture (solid, pattern, necrosis)
Alkushi – 2 grades, architecture and nuclear
Each prognosticates well
Reproducibility of grading
Alkushi (arch+nuclear)
Nielsen (arch)
Nielsen (nuclear)
Zaino (arch)
Zaino (nuclear)
Taylor (arch)
Lax (arch)
Scholten (arch, using Lax)
Inter-observer kappa
2 grade
3 grade
0.76
0.61
0.70
0.55
0.49
0.57
0.97
0.52
0.65
0.55
0.39
0.41
Lymphatic invasion
lymphatic invasion
9
vascular pseudo-invasion
Pathologic Staging (pTNM [FIGO])
Primary Tumor (pT)
___ pTX [--]:
Primary tumor cannot be assessed
___ pT0 [--]:
No evidence of primary tumor
___ pTis [0]:
Carcinoma in situ
pT1 [I]: Tumor confined to corpus uteri
___ pT1a [IA]:
Tumor limited to endometrium
___ pT1b [IB]:
Tumor invades less than one-half of the myometrium
___ pT1c [IC]:
Tumor invades one-half or more of the myometrium
pT2 [II]: Tumor invades cervix, but does not extend beyond uterus
___ pT2a [IIA]:
Tumor limited to the glandular epithelium of the endocervix. There is no
evidence of connective tissue stromal invasion.
___ pT2b [IIB]:
Invasion of the stromal connective tissue of the cervix
pT3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and FIGO IIIA, IIIB, and IIIC
___ pT3a [IIIA]:
Tumor involves serosa, parametria, and/or adnexa (direct extension or
metastasis)
*___ pT3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or metastasis) and/or
cancer cells in ascites or peritoneal washings
___ pT3b [IIIB]:
Involvement of vagina (direct extension or metastasis), rectal or bladder wall
(without mucosal involvement), or pelvic wall(s) (frozen pelvis)
___ pT4 [IVA]:
Tumor invades bladder mucosa and/or bowel mucosa
Regional Lymph Nodes (pN)
___ pNX: Cannot be assessed
___ pN0: No regional lymph node metastasis
___ pN1 [IIIC]: Regional lymph node metastasis
Specify:
Number examined: ___
Number involved: ___
Distant Metastasis (pM)
___ pMX: Cannot be assessed
___ pM1 [IVB]: Distant metastasis
Stage I Corpus Cancer
Pathologic Staging (pTNM [FIGO])
Primary Tumor (pT)
___ pTX [--]:
Primary tumor cannot be assessed
___ pT0 [--]:
No evidence of primary tumor
___ pTis [0]:
Carcinoma in situ
pT1 [I]: Tumor confined to corpus uteri
___ pT1a [IA]: Tumor limited to endometrium
___ pT1b [IB]: Tumor invades less than one-half of the myometrium
___ pT1c [IC]: Tumor invades one-half or more of the myometrium
pT2 [II]: Tumor invades cervix, but does not extend beyond uterus
___ pT2a [IIA]:
Tumor limited to the glandular epithelium of the endocervix. There is no
evidence of connective tissue stromal invasion.
___ pT2b [IIB]:
Invasion of the stromal connective tissue of the cervix
pT3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and FIGO IIIA, IIIB, and IIIC
___ pT3a [IIIA]:
Tumor involves serosa, parametria, and/or adnexa (direct extension or
metastasis)
*___ pT3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or metastasis) and/or
cancer cells in ascites or peritoneal washings
___ pT3b [IIIB]:
Involvement of vagina (direct extension or metastasis), rectal or bladder wall
(without mucosal involvement), or pelvic wall(s) (frozen pelvis)
___ pT4 [IVA]:
Tumor invades bladder mucosa and/or bowel mucosa
Regional Lymph Nodes (pN)
___ pNX: Cannot be assessed
___ pN0: No regional lymph node metastasis
___ pN1 [IIIC]: Regional lymph node metastasis
Specify:
Number examined: ___
Number involved: ___
Superficial myometrial invasion
1) Is the distinction of non-invasive from
inner half invasion reliable?
2) Should invasion be assessed in thirds
or halves of myometrial thickness?
10
endometrium
myometrium
Superficial myometrial invasion
Stage I Corpus Cancer
significance of invasion
Stage 5 year survival rates (FIGO, 2003)
IA 92% inability to distinguish interIB 91% digitations from myo invasion
IC 81% either outer third or outer half
invasion highly significant
(insufficient data to distinguish
which is superior)
Pathologic Staging (pTNM [FIGO])
Primary Tumor (pT)
___ pTX [--]:
Primary tumor cannot be assessed
___ pT0 [--]:
No evidence of primary tumor
___ pTis [0]:
Carcinoma in situ
pT1 [I]: Tumor confined to corpus uteri
___ pT1a [IA]:
Tumor limited to endometrium
___ pT1b [IB]:
Tumor invades less than one-half of the myometrium
___ pT1c [IC]:
Tumor invades one-half or more of the myometrium
pT2 [II]: Tumor invades cervix, but does not extend beyond uterus
___ pT2a [IIA]: Tumor limited to the glandular epithelium of the
endocervix. There is no evidence of connective tissue stromal invasion.
___ pT2b [IIB]: Invasion of the stromal connective tissue of the cervix
pT3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and FIGO IIIA, IIIB, and IIIC
___ pT3a [IIIA]:
Tumor involves serosa, parametria, and/or adnexa (direct extension or
metastasis)
*___ pT3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or metastasis) and/or
cancer cells in ascites or peritoneal washings
___ pT3b [IIIB]:
Involvement of vagina (direct extension or metastasis), rectal or bladder wall
(without mucosal involvement), or pelvic wall(s) (frozen pelvis)
___ pT4 [IVA]:
Tumor invades bladder mucosa and/or bowel mucosa
Regional Lymph Nodes (pN)
___ pNX: Cannot be assessed
___ pN0: No regional lymph node metastasis
___ pN1 [IIIC]: Regional lymph node metastasis
Specify:
Number examined: ___
Number involved: ___
Stage II Corpus Cancer
Significance of true surgical pathologic
staging: a GOG study (Creasman et al, 1999)
148/1180 with clinical stage II (+ECC)
66/148 with disease in the cervix
31/66 with extrauterine disease
35 (24%) with surgical stage II
Recurrence rates at 5 years:
IIA – 18%
IIB – 21%
11
Stage II Corpus Cancer
5 year survival - 75%, lower than Stage I
(FIGO results, 2003)
More often associated with higher grade,
deep myometrial invasion, and
lymphatic invasion than Stage I
Insufficient data to determine whether
Stage II is a significant prognosticator by
multivariate analysis (probably not)
Stage II Corpus Cancer
IIA
IIB
endocervical gland involvement
cervical stromal invasion
Definitions applied in various publications:
IIA - surface epithelium only (Jordan)
IIA – gland involvement only (Fanning, Eltabbakh,
Prat)
IIA – confined to endocervical epithelium (mucosa)
(Clement and Young)
-but endocervix lacks a mucosa
diagnostic reproducibility probably low
(never tested)
how does it involve glands only?
Pathologic Staging (pTNM [FIGO])
Primary Tumor (pT)
___ pTX [--]:
Primary tumor cannot be assessed
___ pT0 [--]:
No evidence of primary tumor
___ pTis [0]:
Carcinoma in situ
pT1 [I]: Tumor confined to corpus uteri
___ pT1a [IA]:
Tumor limited to endometrium
___ pT1b [IB]:
Tumor invades less than one-half of the myometrium
___ pT1c [IC]:
Tumor invades one-half or more of the myometrium
pT2 [II]: Tumor invades cervix, but does not extend beyond uterus
___ pT2a [IIA]:
Tumor limited to the glandular epithelium of the endocervix. There is no
evidence of connective tissue stromal invasion.
___ pT2b [IIB]:
Invasion of the stromal connective tissue of the cervix
pT3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and
FIGO IIIA, IIIB, and IIIC
___ pT3a [IIIA]: Tumor involves serosa, parametria, and/or adnexa (direct
extension or metastasis)
*___ pT3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or
metastasis) and/or cancer cells in ascites or peritoneal washings
___ pT3b [IIIB]: Involvement of vagina (direct extension or metastasis),
rectal or bladder wall (without mucosal involvement), or pelvic wall(s)
(frozen pelvis)
___ pT4 [IVA]:
Tumor invades bladder mucosa and/or bowel mucosa
Regional Lymph Nodes (pN)
___ pNX: Cannot be assessed
___ pN0: No regional lymph node metastasis
___ pN1 [IIIC]: Regional lymph node metastasis
12
Stage III Corpus Cancer:
Are all forms of Stage IIIA
disease equivalent?
Positive peritoneal cytology
Direct invasion to uterine serosa
Adnexal spread or metastases
Stage IIIA Corpus Cancer
+ peritoneal cytology
Milosevic et al, 1992, pooling of literature
17 studies, 3800 patients; incidence – 11%
Often associated with adnexal or nodal
spread, high grade, deep invasion
Univariate analysis – increased risk of
recurrence in most studies
Multivariate analysis (5 studies) – decreased
survival in 3/5
+ cyto as an isolated poor prognostic factor
is rare
Stage IIIA Corpus Cancer
+ adnexal involvement
(Connell et al, 1999)
5 year DFS – 37% overall
Often associated with higher grade,
lymphatic invasion, other extrauterine
disease
5 year DFS - 71% without other
extrauterine spread
Stage IIIA Corpus Cancer
+ serosal involvement (SI)
(Ashman et al, 2001)
5 year DFS – 29%
5 year DFS – 20%, SI + other
extrauterine sites
5 year DFS – 42%, SI only
Are all forms of Stage IIIA
disease equivalent?
5 year recurrence free survival
(Mariani et al, 2002)
+ cytology only
79%
+ adnexa/uterine serosa
57%
(p = 0.04)
(Tebeu et al, 2004)
+ cytology only
+ adnexa/uterine serosa
91%
50%
13
Stage III Corpus Cancer
Stage IIIB – vaginal metastases
Very rare, (less than 1% of corpus cancer
and about 2% of stage III pts)
Vaginal mets often associated with nodal
or distant metastases
Prognosis poor – 5 year survival about 25%
Pathologic Staging (pTNM [FIGO])
Primary Tumor (pT)
___ pTX [--]:
Primary tumor cannot be assessed
___ pT0 [--]:
No evidence of primary tumor
___ pTis [0]:
Carcinoma in situ
pT1 [I]: Tumor confined to corpus uteri
___ pT1a [IA]:
Tumor limited to endometrium
___ pT1b [IB]:
Tumor invades less than one-half of the myometrium
___ pT1c [IC]:
Tumor invades one-half or more of the myometrium
pT2 [II]: Tumor invades cervix, but does not extend beyond uterus
___ pT2a [IIA]:
Tumor limited to the glandular epithelium of the endocervix. There is no
evidence of connective tissue stromal invasion.
___ pT2b [IIB]:
Invasion of the stromal connective tissue of the cervix
pT3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and FIGO IIIA, IIIB, and IIIC
___ pT3a [IIIA]:
Tumor involves serosa, parametria, and/or adnexa (direct extension or
metastasis)
*___ pT3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or metastasis) and/or
cancer cells in ascites or peritoneal washings
___ pT3b [IIIB]:
Involvement of vagina (direct extension or metastasis), rectal or bladder wall
(without mucosal involvement), or pelvic wall(s) (frozen pelvis)
___ pT4 [IVA]:
Tumor invades bladder mucosa and/or bowel mucosa
Regional Lymph Nodes (pN)
___ pNX:
Cannot be assessed
___ pN0:
No regional lymph node metastasis
___ pN1 [IIIC]: Regional lymph node metastasis
Specify: Number examined: ___
Number involved: ___
Stage III Corpus Cancer
Stage III C – pelvic/paraaortic nodal mets
(Mariani et al, 2002)
Stage IIIC often are also Stage IIIA/IIIB
5 year DFS – 33% Stage IIIC with IIIA/B
mostly extranodal failures
5 year DFS – 68% Stage IIIC without IIIA/B
mostly nodal failures
Stage III Corpus Cancer
Stage III C – pelvic/paraaortic nodal mets
5 year DFS – about 65-80% + pelvic node
5 year DFS – about 30% + paraaortic node
Significant survival differences between
microscopic and grossly positive nodes,
resected vs non-resected disease,
radiated vs non-irradiated nodal beds,
and capsular invasion and desmoplasia
Tentative staging conclusions
Stage IA cannot reliably be distinguished from
Stage IB pathologically in many cases
Stage IIA and IIB are poorly defined pathologically
and may not differ prognostically
Stage II is probably not prognostically significant
Stage III disease is very heterogeneous
Stage IIIA alone is heterogeneous
+ cytology alone is rare and probably
significant but with small effect (85%)
+ adnexa is more significant (70%)
+ uterine serosa carries a poor prognosis (30%)
14
Surgical Staging of Corpus
Cancer (EGO, 2008)
Tentative staging conclusions
Stage IIIB (vaginal mets) very rare, poor
prognosis (25%)
Stage IIIC
+ pelvic nodes significant (70%)
+ paraaortic nodes significantly worse (30%)
grossly positive nodes; capsular invasion and
desmoplasia; other extrauterine sites
associated with a much worse outcome
(Stage IIIC limited to nodes usually fails in
nodal area)
Additional prognostic factors
Flow cytometry
Steroid receptors
Markers of apoptosis (BCL-2)
Markers of proliferation
Tumor suppressor genes and oncogenes
Markers of angiogenesis
Potential utility
Steroid receptors
BCL-2
MIB1
Her2/neu
Microvessel density
Stage
IA G123
IB G123
IIA
IIB
IIIA1
IIIA2
IIIB1
IIIB2
IVA
IVB
Characteristics
invasion to endometrium/inner half of myometrium
invasion to outer half of myometrium
positive peritoneal cytology
uterine serosa, adnexal or other pelvic spread
pelvic nodal metastasis (micro)
pelvic nodal metastasis (gross)
paraaortic nodal metastasis (micro)
paraortic nodal metastasis (gross)
vaginal metastases, invasion of bladder or bowel
mucosa
distant, intraabdominal or inguinal node
metastases
Demonstrated utility
FIGO stage
Histologic grade
Cell type
Depth of myometrial invasion
Lymphatic invasion
Tumor ploidy
p53
Unlikely utility
PCNA
S-phase fraction
AgNOR count
15
Objectives
1) Review the biology of the two major types
of endometrial adenocarcinoma
2) Examine the application of and significance
of the CAP template for endometrial
cancer
3) Examine the utility and limitations of the
FIGO staging scheme for endometrial
cancer
4) Examine prognostic factors in endometrial
carcinoma
16
Endometrial Cancer: Who Needs Lymphadenectomy
A Mariani, SC Dowdy, MB Jones, WA Cliby, BS Gostout,
TO Wilson, KC Podratz
An exigent need exists for a paradigm shift in the management of endometrial cancer.
The continuing debate as to whether to perform lymphadenectomy (LND) versus
radiotherapy (RT) exemplifies a modality-based approach to treatment rather than using a
disease-based care pathway. The primary objectives for a revised paradigm should be to
optimize outcomes through minimizing both overtreatment and undertreatment.
Overtreatment can be minimized by identifying patients not requiring LND or RT and
undertreatment minimized by identifying patients benefiting from one or both modalities.
Disease-based therapy should be predicated on anticipated patterns of failure predicted by
pathologic (and/or molecular) determinants. The merits of LND are diagnostic,
prognostic, therapeutic and predictive of the requirement for adjuvant therapy. LND
should be reserved for patients at risk for node metastasis. An absence of nodal
involvement and a 5 year survival of 100% were observed in a cohort of 123 consecutive
patients fulfilling the following criteria: Grade 1/2, endometrioid, < 50% myometrial
invasion and primary tumor diameter < 2 cm. Accordingly, LND is not indicated in these
low risk patients. This group accounted for 20% of the overall population and 29% of
endometrioid patients. Node positivity in the remaining endometrioid population (71%)
was 17%. Thus, for all other endometrioid as well as nonendometrioid patients we
recommend a systematic LND up to the renal vessels. The independent risk factors
dictating pelvic sidewall failure include cervical stromal invasion and lymph node
metastasis (LNM); 5 year failure rates are <1 % in the absence of these factors and 26%
when either or both were present (p<0.001) despite traditional modality based treatment.
Pelvic sidewall failures at 5 years in patients with positive nodes approximated 10% in
our cohort treated with combined systematic LND and adjuvant RT compared to >50%
for patients treated with either LND or RT alone (p<0.01). Furthermore, in the presence
of pelvic LNM, the greater majority of patients had either paraaortic LNM at the time of
surgery or subsequently failed in the paraaortic area. Importantly, in a recently
completed prospective assessment, the majority of patients with paraaortic node
involvement had negative nodes below the inferior mesenteric artery (IMA) while the
greater majority had documented positive nodes above the IMA. Hence, LND is a
determinant for adjuvant therapy including the requirement for extended RT fields
including the paraaortic area whenever LNM is detected in either the pelvic or paraaortic
node bearing regions.
REFERENCES
1.
Podratz KC, Mariani A, Webb MJ. Staging and therapeutic value of
lymphadenectomy in endometrial cancer -Editorial. Gynecol Oncol 70:163-164,
1998.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Mariani A, Webb MJ, Galli L, Podratz KC. Potential therapeutic role of para-aortic
lymphadenectomy in node-positive endometrial cancer. Gynecol Oncol 76:348-356,
2000.
Mariani A, Sebo TJ, Katzmann JA, Keeney GL, Roche PC, Lesnick TG, Podratz KC.
Pretreatment assessment of prognostic indicators in endometrial cancer. Am J Obstet
Gynecol 182:1535-44, 2000.
Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk
corpus cancer: Is lymphadenectomy or radiotherapy necessary? Am J Obstet
Gynecol 182:1506-19, 2000.
Mariani A, Webb MJ, Rao S, Lesnick T, Podratz KC. Significance of pathologic
patterns of pelvic lymph node metastases in endometrial cancer. Gynecol Oncol
80:113-120, 2001.
Mariani A, Webb MJ, Keeney GL, Podratz KC. Routes of lymphatic spread: A
study of 112 consecutive patients with endometrial cancer. Gynecol Oncol. 81:100104, 2001.
Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Predictors of lymphatic
failure in endometrial cancer. Gynecol Oncol.84:437-442, 2002.
Mariani A, Keeney GL, Aletti G, Webb MJ, Haddock MG, Podratz KC. Endometrial
carcinoma: paraaortic dissemination. Gynecol Oncol 92:833-8, 2004.
Mariani A, Sebo TJ, Katzmann JA, Roche PC, Keeney GL, Lesnick TG, Podratz KC.
Endometrial cancer: can nodal status be predicted with curettage. Gynecol Oncol
96:594-600, 2005.
Mariani A, Dowdy SC, Cliby WA, Haddock MG, Keeney GL, Lesnick TG, Podratz
KC. Efficacy of systematic lymphadenectomy and adjuvant radiotherapy in nodepositive endometrial cancer patients. Gynecol Oncol 101:200-208, 2006.
Endometrial Cancer
Surgical Staging
Endometrial Cancer
Surgical Staging
Role of Lymphadenectomy
• Definitive Staging
• TAH/BSO/Peritoneal cytology
• Pelvic/Paraaortic LND*
• Biopsy/Omentectomy
• Cytoreduction (Rx)
Karl Podratz MD PhD FACS
*LND = Lymph node dissection
Endometrial Cancer
Endometrial Cancer
Role of Lymphadenectomy vs Radiotherapy
Annual Incidence Cases and Deaths
Year
ACS Estimates*
Cases
Deaths
1987
2007
35,000 2,900
39,080** 7,400***
• Modality-based therapy*
• Lymphadenectomy
• Radiotherapy
*Traditions, physician preferences,
suboptimal study designs, etc.
Endometrial Cancer
Role of Radiotherapy and Lymphadenectomy
• Treatment paradigm shift
• Minimize overtreatment
–Identify pts not requiring LND
and/or RT
• Minimize undertreatment
–Identify pts benefiting from
LND and/or RT
• Maximize outcomes
*Ca 1987; CA 2007
**11.7% increase; ***155% increase
Endometrioid Endometrial Cancer
Role of Radiotherapy and Lymphadenectomy
• Modality-based therapy
• Radiotherapy vs. lymphadenectomy
• Uterine histology
• Disease-based therapy
• Based on patterns of failure
» Predicted by pathologic determinants
• Selective Lymphadenectomy
• Selective Radiotherapy
• Selective Chemotherapy
1
Endometrial Cancer
Endometrial Cancer
Selective Lymphadenectomy
Selective Lymphadenectomy
(not sampling)
• Lymphadenectomy not indicated*
• Lymph Node Dissection (LND)
• Low risk: Not indicated
• All others: Systematic
• Low risk:
»Endometrioid
»G 1&2
»MI < 50%
»PTD < 2 cm
*Mariani et al. Am J Ob Gyn 2000
Endometrioid Endometrial Cancer
Endometrioid Endometrial Cancer
Low risk: G1/2, < 2 cm, < 50% MI
Low Risk: G 1/2, MI < 50%, PTD < 2 cm
Treatment^
Hysterectomy only
Hyst + LND* +/or RT**
Total
Pt
(no.)
59
64
123
% 5 yr
Survival
100
100
^3/113 recurred (vagina) without RT; all salvaged
• Lymphadenectomy not indicated
• 20% Over all population*
• 29% Endometrioid patients*
*Mariani et al. Am J Ob Gyn 2000
*All nodes negative; **10 RT; 7 for PPC
Mariani et al. Am J Ob Gyn 2000
Endometrioid Endometrial Cancer
Selective Lymphadenectomy
• Lymphadenectomy not indicated
• Low risk: G 1/2, MI < 50%, PTD < 2 cm
• Systematic Lymphadenectomy
• All others (not low risk)
• 17% positive nodes
2
Endometrial Cancer Failures
Endometrial Cancer Failures
Pelvic Lymphatic Failures
Lymphatic Failures
Lymphatic failures according to risk factors
Lymphatic failures according to risk factors
Lymphatic
Failure rate
P
Site
% at 5 years
Value
Pelvic Sidewall
Low risk
High risk*
<1
26
<0.001
Low risk = absence of high risk factors
High risk = *CSI and/or LN mets
Lymphatic
Site(s)
Pelvic Sidewall
Low risk
High risk*
Failure rate
% at 5 years
P
Value
<1
26
<0.001
1
33
<0.001
Para-aortic area
Low risk
High risk**
Low risk = absence of high risk factors
High risk = *CSI and/or LN mets; **LN mets only
Endometrial Cancer Failures
Endometrial Cancer Failures
Paraaortic Lymphatic Involvement
Paraaortic Lymphatic Involvement
• 33% para-aortic failures with
pelvic and/or para-aortic LN
mets
• 47% with positive pelvic LN
either had para-aortic LN
mets or para-aortic failures *
• 47% para-aortic LN mets or
para-aortic failures with
pelvic LN mets*
*Mariani et al 2002 (Mayo series)
*Mariani et al 2002 (Mayo series)
Endometrial Cancer
Endometrial Cancer
Surgical Management*
Quality Assessment LND
Number paraaortic nodes removed per surgeon during phase I
• Hysterectomy, BSO, Peritoneal Cytology,
Pelvic/Para-aortic lymphadenectomy (up to
35
30
• Omit lymphadenectomy if Grade 1 or 2,
endometrioid, MI < 50%, and PTD < 2 cm
• Omit lymphadenectomy if non-invasive
endometrioid regardless of PTD or grade
• Separately submit nodes above & below IMA
• If non-endometrioid, add complete omentectomy,
appendectomy, peritoneal biopsies, cytoreduction
*Mayo prospective accrual 1/2004 to 12/2006
numberpa
renal vessels)
25
20
15
10
5
1
2
3
surgeon
4 5 6
7
Mayo QI Project
3
Endometrial Cancer
Endometrial Cancer
Quality Assessment LND
Surgical Management*
Number paraaortic nodes removed per surgeon during phase II
35
• Objectives of Prospective Rx Algorithm
30
• Prevalence Pelvic LN mets according to
histologic subtype
• Prevalence Para-aortic LN mets with
lymphatic dissemination
• Para-aortic metastatic site frequency as
function of IMA
numberpa
25
20
15
10
5
0
1
2
3
surgeon
4
5
6
7
Mayo QI Project
*Mayo prospective accrual 1/2004 to 12/2006
Endometrial Cancer
Endometrial Cancer
Surgical Management*
Surgical Management*
• 422 patients
• 112 (27%) LND not indicated
• 281 at-risk patients LND
• 15 pelvic (P) LND only
• 1 para-aortic (PA) LND only
• Median # nodes harvested
»90 (80%) no LND
»22 (20%) had LND (all neg)
• 310 (73%) required LND
» Pelvis 35
» Para-aorta 17
»29 (9%) no LND
»281 (91%) had LND
• 63 (22%) positive nodes
*Mayo prospective accrual 1/2004 to 12/2006
Node
Site
PA
P+PA
P
*Mayo prospective accrual 1/2004 to 12/2006
Endometrial Cancer
Endometrial Cancer
Surgical Staging
Surgical Staging
# Pos
n=63*
10
29
24
%
16
46
38
PA 62%
P 84%
*63/281 (22%) at-risk patients had positive nodes
Mayo prospective accrual 1/2004 to 12/2006
Node
Site
PA
P+PA
P
# Pos
n=57*
9
29
19
%
16
51
33
PA 67%
P 84%
*57/265 (22%) at-risk pts had both P+PA LND & + nodes
Mayo prospective accrual 1/2004 to 12/2006
4
Endometrial Cancer
Surgical Staging*
Paraaortic Node Metastases
Skipping Common Iliac Nodes
• 63 (22%) at-risk pts Pos Nodes
• 84% + pelvic nodes
• 67% + paraaortic nodes
71%
»71% com Iliacs neg
*Mayo prospective accrual 1/2004 to 12/2006
Endometrial Cancer
Endometrial Cancer
Surgical Staging*
Surgical Staging*
• 63 (22%) at-risk pts Pos Nodes
• 84% + pelvic nodes
• 67% + paraaortic nodes
»71% com Iliacs neg
»60% neg below IMA
• 63 (22%) at-risk pts Pos Nodes
• 84% + pelvic nodes
• 67% + paraaortic nodes
»71% com Iliacs neg
»60% neg below IMA
»77% + above IMA
*Mayo prospective accrual 1/2004 to 12/2006
Paraaortic Node Metastases
Metastasis above IMA
*Mayo prospective accrual 1/2004 to 12/2006
INVASION OF THE GONADAL VESSELS
or surrounding soft tissue
77%
IMA
28%
5
Endometrial Cancer
Surgical Staging*
Non-Endometrioid Endo Ca (NEEC)
Role of Surgical Staging
• Surgical Staging required
• Lymphadenectomy up to IMA only
• 38-46% PA node Positive cases
missed
• Managed as ovarian
• 422 EC pts Rx’ed surgically*
• 82 (19%) NEEC
• 62% cases node positive below IMA
are node positive above IMA
*Mayo prospective accrual 1/2004 to 12/2006
– 37% Macro extra-uterine disease
– 21% Micro extra-uterine disease
» 25% noninvasive
– 40% Node metastasis
*Mayo prospective series: 1/04-12/06
Endometrioid Endometrial Cancer
Endometrioid Endometrial Cancer
Surgical Management*
Surgical Management*
• 340 (81%) patients
• 112 (33%) LND not indicated
»90 (80%) no LND
»22 (20%) had LND (all neg)
• 228 (67%) required LND
»19 (8%) no LND
»209 (92%) had LND
• 209 at-risk patients LND
• 11 pelvic LND only
• Median # nodes harvested
» Pelvis 36
» Para-aorta 17
• 34 (16%) positive nodes
»10% population
*Mayo prospective accrual 1/2004 to 12/2006
*Mayo prospective accrual 1/2004 to 12/2006
Endometrioid Endometrial Cancer
Endometrioid Endometrial Cancer
Surgical Staging
Surgical Staging*
Node
Site
# Pos
n=32*
%
PA
P+PA
P
6
14
12
19
44
37
PA 63%
P 81%
*32/198 (16%) at-risk pts had both P+PA LND & + nodes
Mayo prospective accrual 1/2004 to 12/2006
• 32 (16%) at-risk pts Pos Nodes
• 81% + pelvic nodes
• 63% + paraaortic nodes
»67% com Iliacs neg
»73% Ipsi neg below IMA
»69% pos above IMA
*Mayo prospective accrual 1/2004 to 12/2006
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Endometrioid Endometrial Cancer
Role of Radiotherapy and Lymphadenectomy
• Treatment paradigm shift
• Minimize overtreatment
–Identify pts not requiring LND
and/or RT
• Minimize undertreatment
–Identify pts benefiting from
LND and/or RT
• Maximize outcomes
Endometrioid Endometrial Cancer
Role of Radiotherapy and Lymphadenectomy
• Modality-based therapy
• Radiotherapy vs. lymphadenectomy
• Uterine histology
• Disease-based therapy
• Based on patterns of failure
» Predicted by pathologic determinants
• Selective Lymphadenectomy
• Selective Radiotherapy
• Selective Chemotherapy
Endometrial Cancer
Surgical Staging
Role of Lymphadenectomy
Karl Podratz MD PhD FACS
7