Papanicolaou was penniless off the ship. He was selling carpets to survive. He was a terrible salesman, and he finally got a research job at Cornell

Transcription

1 La prueba de Papanicolaou: Criterios actuales y conceptos cambiantes The Pap Test: Current Criteria and Changing Concepts Papanicolaou was penniless off the ship. He was selling carpets to survive. He was a terrible salesman, and he finally got a research job at Cornell Rana Hoda Syed Hoda Papanicolaou Cytology Laboratory Cornell University, New York Sid Mukherjee: The Emperor of All Maladies Cervical Cancer: Incidence & Mortality Incidence The Pap Test: biggest success story in cancer screening Mortality American Cancer Society, Pap smear was routine for all women admitted to The New York Hospital in 1939 Pap Cervical Cancer in United States Cervical Cancer in Argentina In USA 12,360 new cases of cervical ca in 2014 ~ 4,000 deaths in 2014 In Argentina, cervical cancer is the #2 cause of cancer deaths in young women Squamous carcinoma is most common 5-year-survival with early detection: >90% Saslow, CA Cancer J Clin 2012 WHO 6 1

2 55 million Pap tests annually 3.5 million abnormal: 7% Eltoum Cancer Cytopathol 2007;111:34 7% Abnormal Pap Tests Transformation Zone HSIL 300,000 Cancer 12,170 LSIL 1,000,000 ASC-US 2,500,000 (4%) >4,000 American women will die of disease in 2014 Copyright 2012 by ASCP Precursors of Cervical Carcinoma Liquid-Based Preparations Thinprep Surepath Copyright 2012 by ASCP DeMay 20 mm 13 mm methanol ethanol Greatest Advance in Pap Test Hoda. Diagn Cytopathol. 2013;41:257 2

3 SurePath _ Monolayer Different planes of focus Flattened clusters 3-dimensional clusters Hoda, Diagn Cytopathol 2012 Endocervical polyp, Nabothian cyst, Tunnel clusters, Diffuse laminar endocervical glandular hyperplasia- Lobular endocervical glandular hyperplasia, Nonspecific endocervical hyperplasia, Microglandular change, Mesonephric hyperplasia, Tubal metaplasia, Tuboendometrioid hyperplasia, Cervical endometriosis, Endocervicitis, Arias-Stella reaction, Secondary glandular atypia, Minor endocervical atypia, Adenocarcinoma in situ, Superficial adenocarcinoma in situ, Borderline invasive adenocarcinoma, Adenoma malignum-minimal deviation adenocarcinoma, Endocervical type adenocarcinoma, Well-differentiated villoglandular papillary adenocarcinoma, Endometrioid adenocarcinoma, Clear cell carcinoma, Mesonephric carcinoma, Adenosquamous carcinoma, Glassy cell carcinoma, Adenoid basal carcinoma, Adenoid cystic carcinoma, Mixed adenocarcinoma, SMILE: Stratified mucin-producing intraepithelial lesion, etcetera Case 1 37-Year-Old Prior Pap Tests Negative Pap, Hyperchromatic Cells Crowded Groups Cells in Strip Cytological Diagnosis Tubal Metaplasia 3

4 Endocervical Cell Ciliated, mucinous, intercalated Tubal metaplasia seen in % of normal endocervix Babkowski, Am J Clin Pathol 1994;101:376 Jonasson, Int J Gynecol Pathology 1992;11:89 AIS: 50 m 75 m 2 2 R Endocervical Cell IIIIIIIII Ciliated Endocervical Cell IIIIIIIII Age: 35+ Glandular Crowding Tubo-endometrioid metaplasia Tubal metaplasia sans cilia, post-cone Palmate Folds 4

5 sterile Nuclear Nipple Progesterone Effect I septic I spinnbarkeit Koizumi, Diagn Cytopathol 1998;15:161 Ramsey II uu II uu Transformation Zone II uu II uu II uu Birth Infancy Puberty Physiological Adult Ectropion Menopause Ectopy Day Gray s Anatomy 90 5

6 360x3 SurePath, 1999, Dimensional Sheets 2-Dimensional Sheets Endocervical Atypia Causes Inflammation and Repair Brush artifact Overinterpretation of tubal metaplasia as Tubal metaplasia AIS or adenocarcinoma can be problematic Lower-segment endometrium Individual atypical cells encountered: Microglandular hyperplasia Composite picture of neoplasia absent Adenocarcinoma in situ Carcinoma Novotny, Acta Cytol 1992;36:1 Ducatman, Diagn Cytopathol 1993;9:98 Jonasson, Int J Gynecol Pathol 1992;1:89 6

7 1? Repair 2 3 Low-Grade Squamous Intraepithelial Lesion, LSIL Adenocarcinoma In Situ 4 5 Benign Endometrial Cells Endometrial Adenocarcinoma 7

8 6 Vermeer High Grade Squamous Intraepithelial Lesion, HSIL Bethesda System Abnormalities in Pap test squamous ASC-US ASC-H LSIL HSIL Case #2 30-year-old woman with previous normal Paps LSIL-H invasive squamous cancer ASC-US, Most cases of ASC Cytological features suggestive of LSIL ~4-5% of all abnormal Pap diagnoses HPV +, ~ 50% HSIL, 5-17% Diagnosis: Atypical Squamous Cells of Undetermined Significance, ASC-US 8

9 Types of ASCUS ASCUS, NOS ASCUS, NOS ASCUS in atrophy ASCUS, atypical parakeratosis Spectrum of lesions ranges from reactive to invasive carcinoma Hoda. Cytojournal Apr 24;5:10 ASC-US Atypical Parakeratosis ASCUS in Atrophy SP ASCUS Features Hormonal Rx ASC-H mimics Candida Koilocyte-like bi- or multinucleation PK Steinman Acta Cytol. 2008;52:279 Moriarty, Archiv Pathol Lab Med 2009;133:1272 SP 9

10 ASCCP Guidelines 2012 ASC-US Screening Guidelines for Prevention & Early Detection of Cervical Cancer, 2012 Repeat 6 & 12 mo Detects 73% HSIL HPV-DNA test Detects 93% HSIL Updated, for Pap screening & in the management of adolescents & young women with abnormal cytology Colposcopy Am J Clin Pathol 2012;137:516 Summary of Recommendations Age < 21 y: No screening HPV test should not be used with ASC-US Age y: Cytology alone x 3y Age 30-65: HPV & cytology cotesting x 5y Age > 65 y: No screening with negative hx After hysterectomy: No screening Human Papillomavirus (HPV) Oncogenic virus that causes >99% of cervical cancer There are of 14 types of high-risk HPV HPV16 or HPV18 infection carries a high risk & are detected in ~70% of cervical cancers Saslow, CA Cancer J Clin Am J Clin Pathol 2012;137:516 Wright & Schiffman NEJM 2003;348:489. Saslow AJCP, 2012;137:516 HPV test is FDA-approved for Primary screening, 2014 Cobas HPV test screening starts at 25 yrs Reflex HPV Test: HR-HPV DNA test, 1999 For triage of ASC-US to determine need for colposcopy Primary Adjunctive Screening: DNAwithPap Test, 2003 Women 30 to detect (-) of HPV Available HPV Tests Hybrid Capture 2 [(HC2), Qiagen, MD) Cervista (Hologic, Bedford, MA) Aptima (Hologic, Bedford, MA) Cobas (Roche System, Pleasanton, CA) 10

11 HC2 vs. Cobas HPV Test Both provide pooled results for hrhpv Cobas HPV Test: Simultaneously provides HPV16/HPV18 identification Less cross-reactivity with lrhpv types Screening with HPV Testing vs. Pap Test for the detection of CIN2 Sensitivity HPV DNA testing ~92% Pap test (LBP) ~60% Specificity HPV DNA testing ~94% Pap test (LBP) ~97% Wright & Schiffman NEJM 2003;348:489. Saslow AJCP, 2012;137:516 Proposed Strategy with Cobas HPV test Prevalence of HR-HPV NILM 18% ASC-US 41% ASC-H 56% LSIL 88% HSIL 96% Cancer 99% Prevalence in ASCUS decreases with age Stoler, AJCP, 2012;137:295. Datta, Ann Intern Med 2008;48:493 Genotyping for HPV16/18 Women with ASCUS & HPV16/18 have a significantly higher rate (43%) of CIN+ than women with ASCUS & non-16/18 HPV HPV genotyping better guides follow-up management Histological Follow-up of HPV+ ASCUS Mean age of HR HPV(+) ASCUS: 29 Negative ~50% CIN % CIN 2/3 5.1% No impact of age or EC/TZS (-) biopsy indicates transient HPV infection Guo. Cancer Cytopathol. 2013;121:79 Armah, Arch Pathol 2009;133:1426, Evans Ca Cyto 2006;106:

12 HPV (-), Cytology ASC-US Risk of precancerous lesions is low Recommend continued routine screening HPV (+), Cytology (-) Repeat co-testing in 12 months HPV 16/18 genotyping Case #3 37-year-old woman All prior Paps: Normal Saslow. Am J Clin Pathol 2012;137:516; Hoda, USCAP abstract 2014 Diagnosis: Atypical Squamous Cells, cannot exclude High-Grade Dysplasia, ASC-H ASC-H Definition, per Bethesda 2001 Changes suggestive of HSIL, but lacks definitive criteria ~5-10% of all ASC % of all Pap diagnoses HPV +, ~ 65% HSIL, 24-68% Selvaggi. Diagn Cyto. 2013;41:943; Sherman, Cancer Cyto 2006;108:298 ASCCP Guidelines 2006 ASC-H SP ASC-H Syncytia, disorganized cells Colposcopy 28% may require > one bx Coarse nuclear chromatin is associated with HSIL, 84% Gupta. Diagn Cytopathol. 2013;41:520 12

13 ASC-H, Hyperchromatic crowded groups ASC-H, Small walnutty atypical metaplastc cells Steep sides & straight edges SP Reactive Histiocytes ASC-H & Histological Correlation MGH ASC-H mimics IUD cell HSIL 52% CIN 2 20% CIN 3 32% Premenopausal 65% Postmenopausal 35% LSIL 23% Benign 25% Selvaggi. Diagn Cytopathol. 2013;41:943 ASC-US ASC-H Case #4 ~90% of ASC HPV 16/18: 50% HSIL 5 17% HPV triage ~10% of ASC HPV 16/18: <85% HSIL 24 68% > colposcopy 28-year-old Woman Routine Pap Test Hoda & Hoda. Fundamentals of Pap Test Cytology,

14 Low-Grade Squamous Intraepithelial Lesion, LSIL LBP do not have a >LSIL & ASC cell rates CAP data: Eversole, Arch Pathol Lab Med. 2010;134:331; Hoda. Diagn Cytopathol. 2013;41:257 ASCCP guidelines 2006 LSIL LSIL LSIL Mimics Reactive Colposcopy LSIL versus Hormonal Changes (Glycogen) SP CIN 1: Natural History Untreated LSIL: ~90% of CIN1 lesions regress within 2 yrs, specially in young ~15 25% may progress to CIN 2/3 Cell blocks from residual LBP vial may detect CIN 2 lesions Hoda. Diagn Cytopathol. 2013;41:257 Catteau. Acta Cytol. 2012;56:247 14

15 CINtec Plus Test (Roche Lab, Heidelberg, Germany) p16ink4a is a cellular kinase inhibitor believed to be a surrogate marker for active HPV infection p16ink4a is a marker for underlying HSIL Ki-67 is nuclear antigen & cell proliferation marker expressed in all cell cycle phases except G0 Coexpression of p16ink4a & Ki-67 identifies deregulated cells CINtec PLUS test p16ink4a stain the cytoplasm brown & Ki-67 stain nucleus red Sensitivity for detection of CIN3 in LSIL samples is high, 95.8% Waldstrom. Cancer Cytopathol. 2013;121:136 CINtec + CINtec in LSIL Borderline Category between LSIL & HSIL LSIL, cannot exclude HSIL (LSIL-H) Atypical keratinized cells LSIL, Cannot Exclude HSIL (LSIL-H) The discrepancy rate between low- and high-grade lesions ranges from 9.8 to 15% TBS, 2008 Elsheikh Cancer Cyto 2006;108:277 LSIL-H HSIL-like cells with unequivocal LSIL 0.15% % Paps Risk of: hrhpv & histologic CIN 2/3 LSIL-H 90% 30% HSIL 96% 70% LSIL 80% 13% ASC-H 54% 17% Case #5 Routine Pap in a 37-year-old with Intra-Uterine Device Baron. Am J Clin Pathol. 2014;141:239 Walavalkar. Cancer Cytopathol. 2014;122:123 15

16 HSIL Uncommon diagnosis, <1% proportion in age 30 years HSIL Carries a high risk of significant disease Biopsy follow-up 70%-75% CIN 2/3 1%-2% Cervical ca High-Grade Squamous Intraepithelial Lesion ~HSIL HSIL Criteria, Bethesda 2001 HSIL, Syncytia Syncytia N:C Metaplastic-type cells Nuclei: coarse chromatin, grooves, irregular HSIL SP HSIL Small walnutty cells, Nuclei 2-3x interm. cell nucleus, Look in empty spaces Bare nuclei 16

17 CIN2 versus CIN3 HSIL Involving Endocervical glands Subclassifying is not crucial 47% of CIN2 Paps were CIN2 on biopsy 53% discordant, most were LSIL on biopsy Howell, Diagn Cytopathol 2004;30:362 SP Features HSIL in EC glands AIS Central cell polarity - + Overlapping + - Nucleoli micro prominent Feathering - + p Apoptosis -/+ + Mitoses -/+ + High N:C + + p16 overexpressed % to 75% of cases have both Kir. J Cytol. 2012;29:121; Wood Diag Cytopathol 2007;35:12 AIS vs HSIL in ECG HSIL Small cell ca Most Common Pap Dx Preceding HSIL on Bx 10% 39% 31% 20% TTF % of Pap Preceding HSIL on Bx were diagnosed as HSIL Hoda, USCAP Poster

18 Missed HSIL cases: Small, pale cells Differential Diagnosis Khalbuss. Cytojournal Aug 30;10 HSIL Immature Squamous Metaplasia Basal Cell Sheets in Atrophy Mimic HSIL LUS vs HSIL Atrophy HSIL, Syncytia Benign Endometrial Cells Mimic HSIL IUD vs HSIL HSIL SP EMC Hoda. Diagn Cytopathol. 2013;41:257 Pinto, Acta Cytol. 2012;56:109. Ge, Acta Cytol. 2012;56:55 18

19 False-Positive for HSIL Atrophic vaginitis Repair HSV ASCCP Guidelines 2006 HSIL Colposcopy AV repair HSV Crothers. Arch Pathol Lab Med. 2014;138:613 Role of HPV Test in HSIL 5-year CIN 2+ risk after 2 negative cotests (hrhpv + Pap) is 1.5% & is more reassuring against recurrent CIN 2+ than either (-) Pap or HPV test alone Segunda parte del Curso Corto Katki. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S78 Case 6 48-year-old woman routine Pap test

20 Squamous carcinoma Differential Diagnosis Repair Non-keratinizing sq. ca SP Squamous Cell Ca, Keratinizing Background in atrophy mimics Squamous Ca Fiber cell Tadpole cell Selvaggi Diagn Cyto 2002:27:362 ASC-US ASC-H 29% increase in incidence in recent years Squamous Ca HSIL LSIL Dr. Pap 20

21 Cellular, mucin, architecture variability Case #7 64-year-old, postmenopausal Prior Paps: negative History: Breast cancer, 2004 Medications: Estrogen 5 years until 2002 Loose sheets, mucinous cytoplasm Nuclei, palisaded, lobate, irregular, nucleoli Cytological Diagnosis Strips, columnar cells & dark oval nuclei Atypical Glandular Cells of Endocervical Origin AGC, EC HPV: Negative AGC: Initial Workup ECC: EMBx: Dissolved on processing Endometrial polyp 21

22 AGC: Subsequent Workup Cervical Cone Minimal Deviation Adenoca of Cervix, MDA Depth of invasion >7mm 6 mos later Invasive Endocervical Adenoca 29% increase in incidence in recent years 1970: ADCA ~12% & sq ca 88% 2000: ADCA ~29% & sq ca 69% ~20% of all invasive cervical carcinoma Earlier detection:? new sampling devices Gross: variable Prognosis:? worse than squamous ca Glandular Cells Bethesda 2001 Atypical Endocervical cells, nos Endometrial cells, nos Glandular cells, nos Atypical Endocervical cells, favor neoplastic Glandular cells, favor neoplastic cells AIS, Adenocarcinoma Zardo, Acta Cytol 2009;53:558 AGC, EC- Follow-up studies Benign 20% - 40% Squamous neoplasia 40% - 80% Neoplasia 0% - 10% EMCa is the most common malignancy Single atypical cells, nuclear membrane, architecture & chromatin pattern are key in distinguishing between neoplastic & benign lesions HR-HPV Test in AGC Sensitivity for significant lesions 83% Specificity 82% HPV 16 and 18 most common types Mulhem, Acta Cytol 2012;56:155. Rijkaart, Lancet Oncol 2012;13:78 Ajit. Acta Cytol. 2013;57:45; Cohen. AJCP 2010;133:799 22

23 Invasive Endocervical Ca, Classification Usual type Mucinous Endocervical, intestinal, signet-ring Endometrioid Clear cell Unusual types MDA Mesonephric Serous Villoglandular papillary adenocarcinoma Modified WHO Classification. Park, Am J Surg Pathol 2011;35:633 ADCA on Pap: Diagnostic Sensitivity AIS 55-70% ADCA 72% HSIL 73% squamous ca 75% Diagnostic Sensitivity for MDA 33% Li, Int J Gynecol Obstet 2010,110:89. Renshaw, Arch Pathol Lab Med 2004;128:153 ADCA on Pap: False-Negative Rate AIS 12% ADCA 9% HSIL 4.6% squamous ca 3.3% 2 to 5 Paps before MDA diagnosis Minimal Deviation Adenocarcinoma of Cervix 1-3% of all cervical adenocarcinomas Median age: 45 years Peutz-Jeghers syndrome (5%) Presentation Vaginal discharge (~70%) Contact bleeding (50%) Hypertrophic or normal cervix No association with HPV infection Li, Int J Gyne Obstet 2010,110:89. Kalir, Int J Gynecol Pathol 2005;24:399 DDX- Benign EC MDA Golden yellow mucin in Paps CS - MDA Large sheet MDA LEGH Khalbuss. Cytojournal Aug 30;10 Conventional PAS & HIK Not seen on LBP Pink mucin in normal EC Hashi, Diagn Cytopathol 2008;36:535. Hata, Diagn Cytopathol 2002;27:80 23

24 Review of Histologically-proven MDA from Treatment of MDA Precise pre-op diagnosis: by Pap & bx remains difficult IHC: CEA, Ki67, AB/PAS, HIK1083 & SMA Radical hysterectomy Tsuji, Histopathol 2011;59:55. Li, Int J Gynecol Obstet 2010,110:89 MDA on Liquid-Based Preps Case #8 36-year-old, Pap, Previous Paps: Negative Clinically: Ectropion Diagnostic dilemma Golden-yellow mucin not seen HPV test & p16 are negative Clean background, HCG & sheets Palisading Nuclei dark, oval, chromocenters, high N/C 24

25 Cytological Diagnosis Biopsies: Negative Adenoca In Situ of Endocervix AIS Colposcopy, Cervical & Endometrial Biopsies Followed Ectropion LEGH Repeat Pap 4 weeks later: AIS AIS Basics At transformation zone Precursor of adenocarcinoma Symptomatic: 3% Incidence 0.61/100,000 Multifocal-multicentric in 50% Rx: Cone, Hysterectomy Cone: AIS Zardo, Acta Cytol 2009;53:558 AIS & ECA Relationship ECA ~43, AIS ~37 AIS > ECA: ~13 yrs CIS to Squamous ca: ~18 yrs AIS usually adjacent to ECA HPV: 18 & 16 Zardo, Acta Cytol 2009;53:558. Plaxe, Gynecol Oncol 1999;75:55 AIS on Pap Sensitivity AIS 55-70% ECA 72% HSIL 73% Squamous ca 75% Cell blocks may detect a significantly more endocervical or endometrial adenocarcinoma compared with the alone (36% vs 8%) Xing. Cancer Cyto. 2014;122:8; Hoda. Diagn Cytopathol. 2011;39:730 25

26 AIS on Pap False-negative AIS 12% ECA 9% HSIL 4.6% Squamous ca 3.3% AIS not detectable by Pap if TZ spared, 54% vs. 25%, p = Kalir, Int J Gynecol Pathol 2005;24:399 AIS Diagnostic Criteria Clean background hyperchromatic crowded groups Columnar monomorphous cells Nuclei crowded, molded Stippled chromatin Nucleoli Feathering, rosettes, strips Apoptosis & mitosis Hoda & Hoda. Fundamentals of Pap Test Cytology, Hyperchromatic crowded groups & sheets Clean background Columnar, crowded cells Rosettes, Nuclei, nucleoli Apoptosis & Mitosis Feathering in Glandular Neoplasia Best criterion, PPV 73% Feathering & HPV+ = glandular neoplasia AIS Differential Diagnosis Tubal metaplasia Lower uterine segment Reactive endocervical cells Invasive ECA HSIL involving endocervical glands Rabelo Santos, Cytopathol 2008;19:34 Conventional Hoda & Hoda, Fundamentals of Pap Test Cytology, Springer,

27 AIS Tubal metapla ECA AIS SurePath Reactive EC LUS 25% to 75% of cases have both HPV test: Glandular Lesions HPV, 16 & 18 Sensitivity for AIS 86% - 100% Sensitivity for ECA 85% - 94% Specificity & NPV 100% & 97% AIS vs HSIL in ECG Acta Cytologica 2012;56:155. Lancet Oncol 2011;12:663 Treatment of AIS Simple hysterectomy Definitive Rx if childbearing complete Cervical cone biopsy with negative margins Fertility preservation F/U with repeat Pap smear and ECC quarterly for 3 years No role for repeat Pap or HPV testing in initial management AIS on Liquid-Based Preps Minimal difference in endocervical neoplasia in conventional & LBP 27

28 Teenager Routine Pap Case 9 17-year-old Two previous normal Paps Pap, smooth-contoured papillary mitosis Cytological Diagnosis Reported as Negative, Reactive Endocervical Cells Biopsy performed feathering ECA Villoglandular Type ECA with Villoglandular Component HPV-negative, p16 focally+ Hysterectomy: 2 positive lymph nodes Why (-)? Cytology of Adenoca of Endocervix Hypercellular Flat sheets Nuclei: large, pleomorphic, macronucleoli Chromatin: uneven Cytoplasm: finely vacuolated Diathesis: necrotic, bloody, proteinaceous Many features of AIS, lack of cohesion Hoda. Diagn Cytopathol. 2010;38:633 28

29 Hypercellular Flat sheets Nuclei dark, nucleoli; Cytoplasm scant SurePath AIS-Like Diathesis Key Feature of Invasion Nucleoli Post-cone: small uniform dark nuclei Adenoca of Endocervix Differential Diagnosis Post-cone changes AIS Endometrial adenoca Squamous cell ca Metastatic adenoca Wood, Diagn Cytopathol 2007;35:12 Hong, Acta Cytol 2001;45:163 ECA in Conventional, SP & General Management Conventional Depends on the stage TAH or conization for early stages Radical hysterectomy, pelvic lymphadenectomy, chemo & radiation for later stages SurePath Bai, Diagn Cytopathol 2000;23:19 Belsley, Diagn Cytopathol 2008;36:232 29

30 2012 Cervical Cancer Screening Guidelines ACS/ACOG/ASCCP 21 yrs: Routine screening starts yrs: every 3-yrs yrs: Screen every 5 years with Pap/HPV >65 yrs: No screening if adequate prior screening Screening guidelines are appropriate as rate of HSIL is very low (0.5%) in young & risk for invasive carcinoma is minimal EC Ca On Liquid-Based Prep Characteristic appearance HPV-status unreliable Cytology: key role in detection Ma. Cancer Cytopathol. 2013;121:432 Case year-old Vaginal Bleeding Granular Background SurePath Diagnosis Endometrial Adenocarcinoma Clinical Presentation of Endometrial Carcinoma Bleeding Watery discharge Increase in size of uterus Pain 30

31 Endometrial Adenocarcinoma on Pap Sensitivity <50% Specificity <97% +Pap in 25% of asymptomatic patients +Pap = higher grade, larger, thicker >5mm Liquid-Based Preparation Better Norimatsu. Diagn Cyto. 2013;4:120; Watanabe Cancer Cytopathol 2009;117:254 Cytology of Endometrial Adenocarcinoma Single cells, tight clusters Variable nuclear size Hyperchromatic nuclei Nucleoli Polarity, less with increase in grade Diathesis in 33% - Sensitivity:73%, Specificity:100% & Positive Predictive Value:100% in endometrial carcinoma Zhou. Diagn Cytopathol. 2013;41:408 Watery Diathesis in Endometrial Carcinoma Conventional Selvaggi, Diagn Cytopathol 2005;33:162 glue-like Cytology of Endometrial Carcinoma Cytoarchitectural criteria more useful, especially for the endometrial hyp; erplasia & low-grade carcinoma For atypical glandular cell diagnoses, the Cellient Cell Block has higher rate of endocervical or endometrial carcinoma diagnoses than, 36% vs 8% Papillary Serous Carcinoma Mixed Mullerian Tumor Zing. Cancer Cytopathol. 2014;122:8; Nambu. Diagn Cytopathol. 2012;40:701 Endometriod Carcinoma Clear CellCarcinoma 31

32 Endocervical Carcinoma Endometrial Carcinoma 2-dimension clusters columnar < cytoplasm bloody diathesis 3-dimension clusters rounded > cytoplasm watery diathesis 7% associated with Actinomyces Use of IUD reduces risk of endometrial carcinoma Cellular immunity is protective? Castellsagué. Lancet Oncol. 2011;12:1023 Lesson Accurate Diagnosis by Pattern Recognition Case Year-Old Post-Coital Bleeding Pap Test, 32

33 Hypercellular Single & Clustered Cells Dirty Necrosis & Malignant Cells Cigar Nuclei Metastases in Paps Rare, <1% Rarely a primary event Usually primary is known Symptom: bleeding Diagnosis:Metastatic Colonic Carcinoma Khalbuss. Cytojournal. 2013;10:17 Hoda. Acta Cytol. 2004;48:586 33

34 Direct Extension, Usually Rectum From Peritoneum, via Fallopian Tube Childs Recurrent colorectal carcinoma detected by routine cervicovaginal pap testing. Low Genit Tract Dis 2005;9:236 Gupta Extrauterine malignancies. Role of pap smears in diagnosis and management. Acta Cytol 1999;43:806 Metastasis, Distant Sites Most Common Metastases in Paps Breast Colon Urinary bladder Endometrium Ovary Mousavi Isolated cervical metastasis of breast cancer: a case report and literature review. J Low Genit Tract Dis 2007;11:276 Otsuka. Br J Cancer. 2013;109:603. Hoda. Diagn Cyto. 2005;33:58 Metastatic Merkel Cell Carcinoma Psammoma Bodies Meisels Spherical bodies, Calcified concentrically Neoplastic: Papillary carcinoma Non-neoplastic: Endosalpingiosis Calcified IUD debris mimics psammoma Gupta. Cytomorphological features of extra-genital metastases in SurePath cervical liquid-based cytology: a series of 8 cases. Cytopathology. 2013;24:123 Hoda, Acta Cytol 2004;48:586 34

35 Consider Metastatic Carcinoma if cytology of lesional cells does not match that of cervix or endometrium Gioradano et al Cervical smear in diagnosis of extrauterine malignancy metastatic to the cervix: 3 case reports Diagn Cytopathol 2010;38:41 In 1951, at the age of 30, Henrietta Lacks, was diagnosed with cervical cancer. Her doctor took a small tissue sample without her consent. A scientist put that sample into a test tube. Although Henrietta died 8 months later, her cells HeLa Cells are still alive HeLa Cells helped develop polio vaccine, & treatment for herpes, leukemia, hemophilia & Parkinson's; & led to cloning, in vitro fertilization, & gene mapping. Since 2001, 5 Nobel Prizes have been awarded for research involving HeLa Cells Rebecca Skloot: The Immortal Life of Henrietta Lacks Rebecca Skloot: The Immortal Life of Henrietta Lacks 35