01 wells cgin
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The Pathology of Glandular Neoplasia of the Cervix
Spanish Congress of Pathology, Cadiz, May 2013
Professor Mike Wells
University of Sheffield
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WHO classification v Cervical Glandular
Intraepithelial Neoplasia (CGIN)
glandularatypia
glandulardysplasia
adeno-carcinoma
in-situ
CGINlow grade
CGINhigh grade
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Glandular dysplasia
“The concept that glandular dysplasia forms a biological spectrum of cervical glandular intraepithelial
neoplasia remains controversial”
Wells et al 2003 Epithelial tumours and related lesions of the
uterine cervix In: WHO Tumours of the breast and female
genital organs
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Is endocervical glandular dysplasia (EGD) a precursor of
adenocarcinoma-in-situ (AIS)?
• EGD is found next to AIS
• EGD is found at a younger age than AIS or
adenocarcinoma
• HPV found in both EGD and AIS
• Higher frequency of EGD than AIS
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High grade CGIN (Adenocarcinoma-in-situ/ severe glandular dysplasia)
• endocervical, intestinal, endometrioid, mixed
adenosquamous types
• tubal - ? reproducible
• frequent coexistent CIN or squamous carcinoma
(approx 50%)
• topography – conflicting data; most cases seem
to involve surface epithelium and superficial
glands near the transformation zone
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Intestinal metaplasia in high grade CGIN
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Low grade CGIN (glandular dysplasia other than severe)
• no well defined criteria – subjective
• natural history – not established
• nuclear and architectural abnormalities of a lesser degree than AIS
• reactive changes – relatively easily recognised
• some cases are HPV 16/18 +ve.
• higher mitotic index than reactive lesions
• neoplastic glycoprotein expression profile
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Stratified Mucin-Producing Intraepithelial Lesion - SMILE
• stratified epithelium resembling CIN in which conspicuous mucin production is present
• mucin production varies from indistinct cytoplasmic clearing to discrete vacuoles
• nuclear and architectural features of neoplasia supported by extensive Ki-67 positivity
• absent keratin 14 and p63 staining consistent with columnar differentiation
Park et al. Am J Surg Pathol 2000; 24: 1414
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PAS DIASTASE MUCICARMINE
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Benign Mimics of CGIN and Adenocarcinoma
• Tubo-endometrioid metaplasia
• Endometriosis
• Microglandular hyperplasia
• Inflammatory atypia
• Mesonephric remnants
• Endocervical hyperplasia
• Tunnel clusters
• Deep cervical glands
• Endocervicosis
• Atypical oxyphil metaplasia
• Adenomyoma
• Radiation effects
• Ectopic prostate
• Arias-Stella effect
• Florid cystic endosalpingiosis
• Cautery artefact
• Mullerian papilloma
• Villous adenoma
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tubal metaplasia
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Mimics of HCGIN – special techniques
MIB1 bcl2 p16INK4a
TEM <10% + cytoplasm Focal +
Endometriosis <10% + cytoplasm Focal +
MEH <10% - -
HCGIN >30% - 100% +
McCluggage. J Clin Pathol 2003; 56: 164
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tubal metaplasia
MIB1
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P16 in cervical glandular intraepithelial neoplasia
• encoded by CDKN2A gene on chromosome 9p21
• strong relationship between p16 expression and HPV-
encoded E6/E7 transcription
• overexpression associated with presence of high-risk
HPV
• all cases of CGIN – p16 positive
• tubo-endometrioid metaplasia and endometriosis may
also show focal p16 immunoreactivity
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p16
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tubal metaplasia –p16
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p16 immunoreactivity in cervical adenocarcinoma
• unusual types of cervical adenocarcinoma are
usually HPV negative
• such tumours may be p16 positive
• p16 is not a reliable surrogate marker of HPV
infection
Houghton et al Histopathology 2010, 57:342-350
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Lobular endocervical hyperplasia (LEGH) and cervical adenocarcinoma
• pyloric gland metaplasia
• atypical LEGH described
• HPV negative
• association with minimal deviation adenocarcinoma
• association with Peutz-Jeghers syndrome
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LOBULAR ENDOCERVICAL GLANDULAR HYPERPLASIA?pyloric gland metaplasia
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Minimal deviation adenocarcinoma
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Adenoma malignum
HIK1083
•HIK1083 – antibody
against a gastric
mucin-type mucin
•gastric phenotpye is
frequently expressed in minimal deviation
adenocarcinoma (MDA)
•possible link between MDA and lobular
endocervical hyperplasia
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Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix
and related glandular lesions
Gastric marker Intestinal marker
HIK1083 MUC6 MUC2 CD10
Adenocarcinoma NOS 7% 23% 14% 7%
Intestinal type adenocarcinoma
23% 69% 85% 15%
MDA 75% 65% 25% 0%
LEH/PGM 95% 75% 15% 0%
Atypical LEH/PGM 78% 67% 11% 0%
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Cervical adenomyomaGilks et al Mod Pathol 1996; 9:220-224
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Ectopic Prostatic Tissue in Cervix
• usually incidental microscopic finding
• usually in ectocervical stroma
• ? developmental anomaly, ? metaplasia
• cribriform and papillary patterns
• usually associated squamous metaplasia
• double cell layer
• positive PSA and PrAP
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PrAP
PSA
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Pitfalls
• markers may be only focally positive
• identical cases which are prostate marker negative
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UNIFYING THEORY
• vaginal tubulosquamous polyp and ectopic prostatic tissue in cervix are same lesion
• ? derived from displaced paraurethral Skene’s glands
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CERVICAL ADENOCARCINOMA –histological variants
• Adenocarcinoma NOS
• Mucinous
endocervical
intestinal
gastric-type
minimal deviation
villoglandular
mucoepidermoid
• Endometrioid
• Clear cell
• Serous
• Mesonephric
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Villoglandular adenocarcinoma
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Villoglandular adenocarcinoma
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Endocervical or endometrial adenocarcinoma?
Endocervical adenocarcinoma
Endometrial adenocarcinoma
Vimentin - ++
Oestrogen receptor
+ Focal ++
CEA ++ + Focal
p16 ++ 100% + <50%
CD10+ 33%
limited luminal
77%
cytoplasm,membrane or both
HPV 66% -
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ER
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p16
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Early invasive adenocarcinoma
• invasive carcinoma with little or no risk of metastatic disease
• suitable for conservative treatment
• histological diagnosis
• synonymous with FIGO stage 1A1 and 1A2 (UK)
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“…I do not know how to make the diagnosis
of microinvasive cancer of the endocervix. I
do not know where the basal lamina is and I
do not know where to measure from. I do not
know what depth constitutes microinvasion.
We do not have the same data for
endocervical invasion that we have for the
lesions in the squamous epithelium”.
Richart R.
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Early invasive/microinvasive adenocarcinoma
“The current 1995 FIGO staging omits specific
reference to glandular lesions in stage 1A. In
addition, there are practical problems in
identifying microinvasive adenocarcinoma
histologically. Nevertheless, it is recommended
that the FIGO classification be adopted”.
Wells et al 2003 Epithelial tumours and related
lesions of the uterine cervix In: WHO Tumours of
the breast and female genital organs
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Andrew Östör 1943-2003
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Criteria for Early Invasive Adenocarcinoma
• obvious invasion to 3mm or less
• usually complete obliteration of the normal endocervical crypts
• extension beyond the normal glandular field
• a stromal response typical of invasive carcinoma
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Early invasive adenocarcinoma
• 0/126 patients treated by radical hysterectomy had parametrial spread
• 5/219 (2.3%) had pelvic lymph node metastases
• 15/436 (3.5%) had recurrence
• 6/436 (1.4%) tumour related deaths
Ostor. Int J Gyn Pathol 2000; 19: 29
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Early invasive adenocarcinoma
• no recurrence in 21 treated by cone alone
• cold knife conisation acceptable treatment if:– adequately sampled
– margins free of disease
• loop excision not acceptable for diagnosis or treatment
Ostor. Int J Gyn Pathol 1999; 19: 29
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Smith et al. Gynecol. Oncol.
2002;85:229-2411• literature review of stage IA cervical
adenocarcinomas
• no difference in survival between Stages IA1 and IA2