Mody. Atypical Glandular Cells(TBS 2001) Adenocarcinoma In Situ(TBS 2001)

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1 Glandular Lesions in Cervicovaginal Cytology Dina R. Mody, MD, FCAP Director of Cytology The Methodist Hospital, Houston, TX Professor of Pathology and Laboratory Medicine Weill Medical College of Cornell University TBS Negative for Intraepithelial Lesion or Malignancy (NILM) Epithelial Cell Abnormality Squamous (ASC-US, ASC-H, LSIL, HSIL,CA) Glandular (AGC, AIS, Adenocarcinomas) Other Other January 11 Atypical Glandular Cells(TBS 2001) Adenocarcinoma In Situ(TBS 2001) Endocervical Endometrial Glandular unqualified(nos) probably neoplastic/ais/ca NOS probably neoplastic Adenocarcinoma In Situ free standing entity(if all criteria) met and not under AGC (Atypical glandular cells) If all criteria not met then under Atypical Endocervicals, probably AIS/neoplastic Hyperchromatic Crowded Groups (HCGs) AIS HSIL ACA Cx Sq ca cx ACA endometrium Other Carcinomas Exodus ball Aggressive endocervical sampl Follicular cervicitis LUS endometrium Tubal metaplasia MGH Atrophy 1

2 Endocervical Vs Endometrial cells Features EndoCx Endometrials Configuration Sheets, strips Cell balls, acini Size Large Small Mitosis Absent May be present Mucin Present Absent Stroma Absent Present Endocervical Adenocarcinoma in Situ (AIS) Precursor lesion of endocervical Adenocarcinoma Nearly 100% HPV + Type 18>16 Arise in endocx or TZ glands Surface and glandular epithelium involved Endocervical AIS Extent: Single focus or all quadrants 50% have associated SIL or Invasive Sqca Colposcopy usually normal or SIL related changes Histologically 5 types Cytologic diagnosis based on architecture and nuclear features Endocervical AIS/HGIL Cellular..Crowded sheets, strips,gld Configuration openings, torn glands, rosettes, palisades. Nuclei..Oval, elongated, hyperchromatic Nucleoli...Inconspicuous Cytoplasm..Granular Background...Clear/intact blood Conventional ThinPrep AIS strips Surepath 2

3 AIS Conventional Vs Thin Prep Vs SurePath AIS Conventional Vs Thin Prep Vs SurePath Features Conv TP SP Large sheets + + +/- 3D groups Feathering + subtle + Rosettes + subtle +sub Strips + +/- ++ Single cells Features Conv TP SP Nuclear shape oval roundov Nu crowd Chromatin Hyper Hyper Hyper even open Nucleoli Incons + +/- Cellularity +++ Variable Variable Helpful Cytologic Criteria AIS Vs Invasive Endocervical Adenocarcinoma (ACA) Reactive AIS Inv Adca Strips Feath Rosettes Nu Over DiTomasso, Ramzy, Mody. Acta Cytol 1996; Many features of AIS in early invasive ACAs Nuclear pleomorphism and irregularity Chromatinic clearing Nucleoli Loss of polarization Three dimensional/acinar groupings Single intact malignant cells Mitosis Tumor Diathesis 3

4 Adenoma Malignum (Minimal deviation Adenocarcinoma of the Cervix) 1-2% of of endocervical adenocarcinoma Extremely well differentiated and hence difficult to recognize on small biopsies Barrel cervix and advanced disease at presentation No association with HPV Some reports that precursor lesion may be endocervical tunnel clusters/hyperplasia Adenoma Malignum Average age at presentation 42 yrs 11% associated with Peutz-Jeghers syndrome 50% with concominant ovarian mucinous tumor (?primary Vs mets from Cervix) Glands with small basally located pale nuclei, CEA+, no stromal response but infiltrate deeply. Rare abnormal cells/papillary surface or desmoplastic response HPV Type Specific Distributions in Adeno & Squamous Cell Carcinomas HPV33 HPV35 H i g h R i s k H P V a n d C e r v i c a l A d e n o c a r c i n o m Author Positive Method Andersson 71% PCR L1&E6 a s HPV59 HPV45 HPV18 HPV16 Squamous Ca Adenoca Casellsague 87.4% PCR G5+/6+ Andersson S et al. European J of Cancer 2001; Casrellsague et al. JNCI 2006; Castellsague et al. JNCI. 2006; High Risk HPV Positive Cervical Adenocarcinomas and Age Mimics of Endocervical Adenocarcinoma and AIS <39 yrs % Positive Andersson A et al. European J of Cancer 37 (2001) Tubal Metaplasia High grade Squamous Intraepithelial Lesion Microglandular Hyperplasia LUS endometrium Aggressive endobrush sampling Repair, Polyps, Hormonal effects Radiation 4

5 TUBAL METAPLASIA Vs AIS Features Tubal meta AIS Cellularity Scant Cellular Honeycombing Many Rare Feathering Rare/abs Common Strips Rare/abs Common Single cells Many Rare T.Bars/cilia Present Absent Nuclei Round/oval Oval/cigar Chromatin Normo Hyperch MICROGLANDULAR HYPERPLASIA Most look like normal endocervicals Repair like configuration Full spectrum of cell sizes within group Nuclei nl or increased in size. Nucleoli may be present and prominent. No mitosis Normo or slight hyperchromasia. Rarely pyknosis Cytoplasm abundant, fine, vacuolated. Pseudoparakeratosis HSIL Vs AIS Features HSIL AIS Strips & Rosettes Absent Present Gland forms Absent Present Feathering Absent Present Polarity Lost Maintain Nu Shape Round/irreg Oval/cigar Chromatin Coarse Even Cytoplasm Dense Even Background Isolated cells Rare/abs 5

6 Significant Criteria, ThinPrep LUS ENDOMETRIUM Nu Crow Strips Feath Rosettes Reactive HSIL AIS Ozkan F, Ramzy I and Mody DR: Glandular lesions of the Cervix on Thin-Layer Pap Tests. Acta Cytol. 48; , 2004 Configuration Tissue fragments, sheets, +/- gland openings. Stromal cells Cell size Small, 2.5 X Int nucleus Sheets Appear crowded with min to no nuclear overlap in plane of focus. Gland openings +/_ Feathering Absent Palisading Absent Mitosis May be present Mucin Absent M i m i c s o f Endocervical Adenocarcinoma, AIS and AGC Tubal Metaplasia High grade Squamous Intraepithelial Lesion Microglandular Hyperplasia LUS endometrium Aggressive endobrush sampling Repair, Polyps, Hormonal effects Radiation Menstrual Pap test ATYPICAL GLANDULAR CELLS Definition Cells showing either endometrial or endocervical differentiation displaying nuclear atypia that exceeds obvious reactive or reparative changes but lacks unequivocal features of invasive adenocarcinoma or adenocarcinoma in situ ATYPICAL ENDOCERVICAL CELLS, favor neoplastic Definition Cells showing endocervical differentiation that QUALITATIVELY OR QUANTITATIVELY fall short of an interpretation of invasive endocervical adenocarcinoma or adenocarcinoma in situ 6

7 A T Y P I C A L E N D O C E R V I C A L C E L L S (Probably Neoplastic) Sheets, strips, rosettes Nu crowding, overlap, Incr N/C ratio Ill-defined cell borders Palisading, Feathering, stratification Hyperchromasia with even chromatin Nucleoli Inconspicuous, Mitosis Clean or slightly bloody background Atypical Endocervical cells, favor neoplastic/ais AGUS (Endometrial) Small groups of 5-10 cells Nu slight enlarged, small nucleoli Slight hyperchromasia Ill-defined cell borders, Scant cytoplasm, vacuoles+/_ AGUS (Endometrial) Small groups of 5-10 cells Nu slight enlarged, small nucleoli Slight hyperchromasia Ill-defined cell borders, Scant cytoplasm, vacuoles+/_ AGC Reporting Rates, CAP 2002 Type Percentile Reporting Rate (%) Mean 5 th 50 th 90 th 95 th Conv TP SP All Davey, Neal, Wilbur, Colgan, Styer, Mody. Arch Pathol Lab Med (2004)

8 AGUS Reporting Rates and Follow- up(%) Histologic Follow up of AGC in Postmenopausal Women Study Rate SIL AIS EMH CA Goff Zweiz Eddy Veljo CAP BCM Davey D, Woodhouse S, Styler P, Stasny J and Mody D. Arch Pathol and Lab Med 124(2): , 2000 Percent of Cases Cx Polyp Endm Polyp EMH EMCA Other Ca ADM SIL ATYPICAL ENDOMETRIALS & AGE AGC follow-up and HPV Typing Tissue Diagnosis <59 yrs >59 yrs Benign Endometrium 59.1% 15.2% Endometrial Polyp 9.1% 13% Endometrial Hyperplasia 12.5% 8.7% Adenocarcinoma 9.1% 41.3% Insufficient Tissue 10.2% 21.7% Cherkis RC et al ZhaoC, Florea, Austin RA. Arch Pathol lab med 134;2010 AGC follow-up and HPV Typing Endometrial Carcinoma ZhaoC, Florea, Austin RA. Arch Pathol lab med 134;2010 Age Cellularity Configuration Nuclei Nucleoli Cytoplasm Background Peri & post menopausal Low Loose cell groups, acini, papillae Round, vesicular Multi/macro Scant, cyanophilic Diathesis 8

9 Endometrial Hyperplasia Mimics of Endometrial Adenocarcinoma Age Cellularity Configuration Nuclei Chromatin Nucleoli Cytoplasm Background Peri & post menopausal Scant Tight cell balls or mod acini Small, round Vesicular/ mild hyperchroma Absent/micro Scant, cyanophilic Increased EE for age Hyperplasia Arias Stella Reaction & Pregnancy Endometrial & Endocervical polyps Cervical Small cell carcinoma IUD changes Fixation & staining artifacts Radiation changes Post menopausal atrophy and bare nuclei S m a l l C e l l U n d i f f e r e n t i a t e d C a r c i n o m a o f the Cervix Uncommon malignancy of cervix Age range Coexist with adenocarcinoma (more frequently) or Squamous cell ca or SIL Type 18 or 16 in almost all cases Falls in the family of Neuroendocrine carcinoma of the cervix(carcinoid, atyp carcinoid, small cell ca, large cell NE ca) ThinPrep small cell Carcinoma Small Cell Undifferentiated Carcinoma of the Cervix Cytologic diagnosis difficult and dd includes HSIL and lymphoma Moulding may be difficult to see on liquid based Chromogranin, synaptophysin, CD56, NSE +. Keratin -, LCA- Propensity for lymphovascular invasion and poor prognosis Differential Diagnosis of Small Cell Undifferentiated Carcinoma of the Cervix Diagnosis Immunohistochem Sm cell ca Chr, Syn+, P63- Sq cell ca P63++, chr, syn Basaloid ca same as above PNET O13/Cd99 Lymphoma LCA, B&T markers Melanoma S100, HMB45, MelanA+ 9

10 Extrauterine Carcinomas on PAP smears Origin of primary Location and extent of spread Patency of fallopian tubes Ascites Follicular Cervicitis on liquid based Tumor Diathesis Endometrial Ca 92.5% Endocervical ca...85% Extrauterine Ca 19.7% NORMAL ENDOMETRIALS & AGE Tissue Diagnosis <59 yrs >59yrs Benign Endometrium 49.6% 22.4% Endometrial Polyp 10.7% 13.8% Endometrial Hyperplasia 11.6% 15.5% Adenocarcinoma 6.6% 20.7% Insufficient 21.5% 27.4% From Cherkis RC et al. 10