Diagnostic Aspects and Proteomic Anlysis of Uterine Flush ...
Diagnostic Problems In Uterine Curettings
Transcript of Diagnostic Problems In Uterine Curettings
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Pacific Northwest Society of
Pathologists
Vancouver, B.C.
September 26, 2015
Teri A. Longacre, M.D.
Stanford University, Stanford, CA
Endometrial Metaplasia,
Hyperplasia & Other Cancer
Mimics: a Consultant’s
Experience
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Disclosure of Relevant Financial Relationships
Scientific Symposiums International requires that anyone in a position to influence or control the content of all CME activities disclose any relevant relationship(s) which they or their spouse/partner have, or have had within the past 12 months with a commercial interest(s) [or the products or services of a commercial interest] that relate to the content of this educational activity and create a conflict of interest. Complete disclosure information is maintained by Scientific Symposiums International and has been reviewed by the CME Advisory Committee.
Teri Longacre declares no conflict(s) of interest to disclose.
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Endometrial Metaplasia
• Endometrial glandular epithelium that is
replaced by other types of cells which
are either not seen or very rarely seen
in normal endometrial glands
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.
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Metaplasia • Ciliated cell metaplasia (change)
- with eosinophilic features
• Eosinophilic metaplasia
• Mucinous metaplasia
• Papillary syncytial metaplasia
- with eosinophilic features
• Simple & complex papillary
proliferations
- with eosinophilic features
• Squamous/morular metaplasia
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Ciliated Cell Metaplasia
• Ciliated cells normal in surface endometrium, but not in glands
• May have nucleo-megaly & mild atypia
• Mitotic figures usually absent
• Often mixed with columnar eosinophilic cells: eosinophilic or pink cell change
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MICRO: Normal Ciliated cells
- 2
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MICRO: Normal Ciliated cells
- 1
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MICRO: Ciliated metaplasia
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MICRO: Ciliated metaplasia
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Cilated Cell Carcinoma: Does It
Exist?
• Rare – pathologic curiosity
• Low grade
• Almost uniformly favorable prognosis
• Better to err on conservative side: atypical
hyperplasia with extensive ciliated cell
change (metaplasia), cannot exclude very
well differentiated adenocarcinoma
Hendrickson MR, Kempson RL. Ciliated carcinoma--a variant of
endometrial adenocarcinoma: a report of 10 cases. Int J Gynecol
Pathol 1983;2:1-12
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Eosinophilic Metaplasia
• Very common
• Eosinophilic, granular
cytoplasm – usually
columnar cells
• Often mixed with ciliated
metaplasia
• May be associated with
mucinous metaplasia
• Often mistaken for
carcinoma
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MICRO: Ciliated metaplasia
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MICRO: Eosinophilic
metaplasia
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MICRO: Ciliated metaplasia
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Mucinous Metaplasia
• Common
• Requires presence of
intracytoplasmic mucin
• Often focal & mixed in
postmenopausal women
• Must distinguish from
mucinous carcinoma
• Localization issues:
cervix
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Mucinous Metaplasia 05-12436
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Mucinous Metaplasia 05-12436
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Mucinous EndomCa 05-6769
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Minimal Deviation Adenocarcinoma
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Mucinous Metaplasia vs Carcinoma
• Mucinous carcinoma may be cytologically very low
grade – significant overlap with atypical mucinous
metaplasia (= atypical hyperplasia)
• Distinction based on architectural complexity &
less commonly, cytology
• In limited samplings, fragmented samplings or
borderline cases, always consider possible
underlying more significant endometrial lesion or
cervical lesion – more about this later
• Beware of isolated mucinous surface metaplasia!
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Mucinous Metaplasia vs
Carcinoma: Strategy
• If you can localize it to the endometrium:
Complex endometrial hyperplasia with
extensive mucinous metaplasia, cannot
exclude well differentiated
adenocarcinoma (see comment)
• If you are not sure if it is arising in cervix
vs endometrium: Complex mucinous
proliferation (see comment)
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Papillary Syncytial Change
(Metaplasia) • Papillary syncytial change associated
with stromal breakdown, atrophy,
karyorrhectic debris
• Papillary syncytial metaplasia occurs
over surface of endometrium, may be
extensive, often mixed epithelial types
• May overlie atrophy, hyperplasia or
carcinoma
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MICRO: Papillary syncytial
metaplasia
Papillary Syncytial Change
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Papillary Metapl 05-19091 Papillary Syncytial Metaplasia
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Pap Syn AH 05-18876
Papillary Syncytial Metaplasia
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Papillary Syncytial Metaplasia
p53
BE WARY OF THE p53 STAIN!!!
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p16
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Papillary Syncytial Metaplasia
• Decreased expression of ER
• Increased expression of p53 (although still
wild-type staining) and p16, the latter
marker typically being diffusely positive
• Low MIB1 proliferation index
• In problematic cases, IHC may result in a
misdiagnosis
Int J Gynecol Pathol 2012;31:206-10
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Papillary Syncytial Metaplasia
• Analogous to “icing on a cake”
• Can overlie atrophy, hyperplasia or
carcinoma
• May occur in up to 15-20% of carcinoma
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Simple Papillary Proliferations
• Atrophic, weakly proliferative, or
proliferative cells without atypia lining
coarse connective tissue papillary cores
• Spectrum of metaplastic changes
• Frequently focal, in endometrial polyps in
atrophic endometria
• “Benign papillary hyperplasia/proliferation”
Am J Surg Pathol 2013;37:167-77
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Simple Papillary Proliferation
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Complex Papillary Proliferations
• May be associated with concurrent or
subsequent endometrial hyperplasia and
carcinoma
• Analogous to atypical hyperplasia (even in
the absence of significant cytological atypia)
• “Complex papillary hyperplasia/proliferation"
Am J Surg Pathol 2013;37:167-77
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p53
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Papillary Problems: Strategy
• Mixed epithelium argues benignancy
• Some degree of cytologic atypia is
permitted in metaplastic papillary lesions
(even expected) – but marked
nucleomegaly & pleomorphism is not
• Serous carcinoma is a cytologic diagnosis
• p53 & p16 should be used with caution
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Squamous-Morular
Metaplasia
• May be seen in
endometria of all types
• Morules vs keratinized
epithelium
• Necrosis in morules is
not evidence of
malignancy
• Estrogenic states
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p16
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MICRO: Necrosis in morules
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Squamous Caveats • Sheets of epithelium don’t necessarily
mean malignant – common cause for misdiagnosis of “grade 2 adenocarcinoma”
• Squamous elements are non-informative with respect to ‘benign / malignant’ (atypical hyperplasia vs. grade I adenocarcinoma)
• Recommend re-sampling, imaging when underlying glandular architecture cannot be evaluated
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Clear Cell (Secretory) Change
• Secretory endometrioid
proliferations
• Non-specific clearing
due neither to mucin nor
glycogen
• Glycogen-rich squamous
proliferations
• May be secondary to
hormonal therapy
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EndomCa with Pill 05-19676
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EndomCa with Pill 05-19676
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Clear Cell Change: Differential
Diagnosis
• Clear cell carcinoma – very uncommon in
the endometrium
• Low grade mucinous endometrial or
endocervical carcinoma
• Exclude metastases – rare, but they do
occur
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The Pathology Report
• Metaplasia can be complex – doesn’t
necessarily imply hyperplasia
• Hyperplasia should have increased gland
to stroma ratio (3:1)
• Be sure the sample is representative – not
always easy to do
• Exclude special variant cancer…to be
continued
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Endometrial Hyperplasia
• Increased gland proliferation
• Greater than 3:1 gland to stroma ratio
• Can be focal…clinical significance
uncertain
• Can be defined by exclusionary criteria –
i.e. not cancer
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Basic Architectural Patterns
• Small crowded (budding) glands
• Macroglands
• Exophytic papillae: villus (or
villoglandular) and non-villus
(papillary)
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Architecture
Small (budding)
glands
Macroglands
Exophytic papillae
Am J Surg Pathol.1995; 19:371-406
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High =
Carcinoma
Low =
Complex
Hyperplasia
Architecture
Longacre et al, AJSP 1995; 19:371-406
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Hyperplasia
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Hyperplasia
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Borderline, Cannot Exclude
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EndomCa with Pill
Endometrial Carcinoma
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CxAdCa in EMB 05-19281
Hyperplasia
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Borderline, Cannot Exclude
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Endometrial Carcinoma
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MICRO: Villoglandular
hyperplasia
Borderline, Cannot Exclude
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MICRO: Villoglandular
carcinoma
Endometrial Carcinoma
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Atypical Endometrial Hyperplasia
• Loss of nuclear polarity
• Nuclear rounding
• Nuclear clearing with vesicular chromatin
pattern
• Prominent nucleoli
• Eosinophilic cytoplasm
Cancer 1985;56:403-412
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EndomCa with Pill
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The Pathology Report
• Complex vs simple hyperplasia no longer
a requirement (WHO 2014)
• Atypical vs non-atypical – atypia should be
fairly diffuse
• If focal atypia, exclude focal low-grade
carcinoma arising in hyperplasia
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Indications For Conservative
(Medical) Management
• Young women who wish to preserve their
fertility
• Women with severe comorbidities – may
be only option
• Borderline lesions, e.g. atypical polypoid
adenomyoma, other weird polyps, “focal
hyperplasia”, etc
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Conservative (Medical)
Management: The Problem
• Few controlled, prospective long-term
studies
• Non-uniform patient selection
• Non-uniform pathology selection
(nonatypical hyperplasia vs atypical
hyperplasia vs carcinoma)
• Non-uniform pathology documentation
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Conservative (Medical)
Management:The Problem
• Non-uniform treatment (drug, dose, duration)
• Patient compliance with oral progestins
• Non-uniform documentation of response
• Risk of relapse for responders not well
delineated
• Efficacy of office biopsy versus curettage not
studied in this setting
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Conservative (Medical)
Management
• Oral Progestin Therapy
• Levonorgestrel-releasing Intrauterine
System (LNG-IUS)
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Oral Progestin Therapy
• Side effects
• Requires compliance
• Type of progestin product variable
• Optimal dose not well defined
• Duration of treatment not well defined
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Levonorgestrel-releasing
Intrauterine System (LNG-IUS)
• Locally acting
• Increased effect on endometrium
• Improved compliance
• Less side effects
• Still relatively new treatment
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Response Rate • Depends on pathology (but data conflicting):
– Nonatypical hyperplasia > atypical hyperplasia >
endometrioid carcinoma
• Depends on menopausal status:
– Mean time to regression 7.5 months in premenopausal
women (range, 4-16 mos)
– Mean time to regression 6.8 months in postmenopausal
women (range, 4-10 mos).
– Postmenopausal women may have better overall
response than premenopausal, but data conflicting
Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-
534; Gynecol Oncol 2012;125:477-82
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TREATMENT EFFECTS
• Architectural-stromal changes
• Metaplastic changes
• Cytological changes
Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-534
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Architectural-Stromal
Changes
• Predecidual change
• Decreased gland confluence and
complexity
• Papillary or cystic architecture
Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-534
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Cytological Changes
• Decreased nuclear size
• Decreased cytologic atypia
• Nuclear membrane rounding
• Chromatin finer and more homogenized or
smudged
• Nucleoli indistinct or absent
• Mitotic figures decreased or absent
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Evaluation of Treated
Hyperplasia/Carcinoma
• Compare prior, pre-treatment biopsy & all
interval biopsies whenever possible
• Evaluate entire specimen – ensure it is
representative
• Consider level sections (persistence of
hyperplasia/carcinoma may be focal)
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Evaluation of Treated
Hyperplasia/Carcinoma
• No response
• Partial response
• Complete response (regression)
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No Response*
• No progestin effect – i.e., no stromal
predicuation or metaplasia over and above
pre-treatment
• Gland complexity similar to pre-treatment
biopsy
• Cytological atypia similar to pre-treatment
biopsy (if present)
*Requires at least 6 mos treatment
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Complete Response
• Atrophy of glands
• Proliferative or secretory pattern
• Edematous fibrotic stroma
• Stromal pseudodecidualization
• No evidence of hyperplasia/carcinoma –
depends on initial diagnosis
• No cytological atypia
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Partial Response
• Decreased gland complexity with
increased metaplasia
• Persistent atypia may be present, but
decreased compared to prior
• Often focal residual gland complexity –
must exclude focal process pre-treatment
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Classification of Progestin-treated
Lesions of the Endometrium
Diagnosis Description
Progestin-treated nonatypical
hyperplasia
No cytologic atypia. Crowded,
back-to-back glands and/or a
confluent glandular pattern
Progestin-treated atypical
hyperplasia
Cytologic atypia. Crowded,
back-to-back glands that lack
a confluent glandular pattern
Progestin-treated well-
differentiated carcinoma
Cytologic atypia. Confluent
glandular pattern (cribriform
and/or papillary pattern).
Modified from Am J Surg Pathol 2007;31:988-998
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Poor Prognostic Signs*
• Persistence of cytological atypia
• Complex papillary architecture
• Cribriform architecture - if more than minor
element
Provided sufficient progestin
treatment (dose, at least 6 mos duration, etc)
Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-534
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Cribriform Architecture
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Cribriform (higher magnification)
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The Pathology Report
• Note whether sampling is adequate
• Note whether progestin effect is present
• Compare priors !!!
• Report all findings – requires microscopic
description
• Comment required in almost all cases
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Endometrial Atrophy
• Common cause of post-menopausal
bleeding (approximately 25% of cases)
• Paucity of tissue in an atrophic
endometrial biopsy or curettage specimen,
is not insufficient or inadequate
• In the appropriate clinical setting, the scant
tissue is likely to be the only tissue present
and is therefore representative of the
endometrium (e.g., “good scrape, but
scant tissue”).
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Atrophy
• Atrophic and weakly proliferative
appearing endometrium is abnormal
during the reproductive years, unless there
is a history of hormonal medication or
premature ovarian failure.
• If the pathologist is unable to assign an
etiology for a scant and/or atrophic
specimen in this setting it is completely
appropriate to make a diagnosis of
insufficient for evaluation.
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Atrophy
• May see enlarged, atypical cells
• Often smudged nuclei
• Absent or rare mitotic figures
• Suggest further evaluation
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Benign polyp with torsion &
surface atypia mimicking
SEIC
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MICRO: EIN
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Benign Polyp vs Serous Endometrial
Intraepithelial Carcinoma (EIC)
• Normal endometrial
(often atrophic) glandular
stucture is preserved
• Marked nuclear atypia,
enlargement, and
hyperchromasia
• Strong nuclear p53 (be
wary!)
• High grade serous
carcinoma elsewhere
• Degenerative changes in
surface endometrium
may masquerade as
SEIC in uterine sampling
• Paucity of mitotic figures
• Absence of strong
nuclear p53
• If uncertainty remains,
re-sampling may resolve
problem
Benign Polyp SEIC
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Stanford University
Thank you