1

Rana HodaSyed Hoda

Papanicolaou Cytology LaboratoryCornell University, New York

The Pap Test: Current Criteria and Changing Concepts

La prueba de Papanicolaou: Criterios actuales y conceptos cambiantes

“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…”

Sid Mukherjee: The Emperor of All Maladies

Cervical Cancer: Incidence & Mortality

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Incidence

Mortality

American Cancer Society, 2014

The Pap Test:biggest success story in

cancer screening

“Pap”

Pap smear was routine for all women admitted to The New York Hospital in 1939Pap smear was routine for all women admitted to The New York Hospital in 1939

Cervical Cancer in United States

In USA

12,360 new cases of cervical ca in 2014

~ 4,000 deaths in 2014

Saslow, CA Cancer J Clin 2012

Cervical Cancer in Argentina

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%

WHO 6

2

55 million Pap tests annually

3.5 million abnormal: 7%

Eltoum Cancer Cytopathol 2007;111:34

ASC-US 2,500,000 (4%)ASC-US 2,500,000 (4%)

LSIL 1,000,000

HSIL 300,000

7% Abnormal Pap Tests

Cancer 12,170

>4,000 American women will die of disease in 2014

Transformation Zone

Copyright © 2012 by ASCP

Precursors of Cervical Carcinoma

DeMay

Copyright © 2012 by ASCP

Liquid-Based Preparations

20 mm 13 mmmethanol ethanol

Thinprep Surepath

Greatest Advance in Pap Test

Hoda. Diagn Cytopathol. 2013;41:257

3

ThinPrep 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, Non-specific endocervical hyperplasia, Microglandularchange, 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, Endometrioidadenocarcinoma, Clear cell carcinoma, Mesonephriccarcinoma, 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, ThinPrep

Crowded GroupsHyperchromatic Cells

ThinPrep

Cells in Strip

ThinPrep

Cytological DiagnosisTubal Metaplasia

ThinPrep

4

Tubal metaplasia seen in 30-100% of normal endocervixBabkowski, Am J Clin Pathol 1994;101:376

Jonasson, Int J Gynecol Pathology 1992;11:89

Ciliated, mucinous, intercalated

R

Endocervical Cell

50m2AIS: 75m2

IIIIIIIII

Endocervical Cell

Age: 35+

IIIIIIIII

Ciliated Endocervical Cell

Tubo-endometrioid metaplasiaTubal metaplasia sans cilia, post-cone

_____Glandular “Crowding”

Palmate Folds

5

sterile

I“septic”I“spinnbarkeit”

Nuclear “Nipple”

Progesterone Effect

Koizumi, Diagn Cytopathol 1998;15:161

Ramsey

uuII uuII uuII

uuII uuIIBirth Infancy Puberty

Adult Ectropion Menopause

Transformation Zone

Physiological Ectopy

360

Day 14

Gray’s Anatomy

90

6

360x3

SurePath, 1999

3-Dimensional Sheets 2-Dimensional Sheets

ThinPrep, 1996

Endocervical AtypiaCauses

_______________________________________________________________________________________________

Inflammation and RepairBrush artifactTubal metaplasiaLower-segment endometriumMicroglandular hyperplasiaAdenocarcinoma in situCarcinoma Novotny, Acta Cytol 1992;36:1

Ducatman, Diagn Cytopathol 1993;9:98Jonasson, Int J Gynecol Pathol 1992;1:89

Overinterpretation of tubal metaplasia as AIS or adenocarcinoma can be problematic

Individual atypical cells encountered:Composite picture of neoplasia absent

7

?

1

Repair

2

Low-Grade Squamous Intraepithelial Lesion, LSIL

3

Adenocarcinoma In Situ

4

Benign Endometrial Cells

5

Endometrial Adenocarcinoma

8

6

High Grade Squamous Intraepithelial Lesion, HSIL

Vermeer

Bethesda System Abnormalities in Pap test

ASC-US ASC-H LSIL HSIL

squamous

invasive squamous cancer

LSIL-H

Case #2_________________________________

30-year-old woman with previous

normal Paps

TP

Diagnosis: Atypical Squamous Cells of Undetermined Significance, ASC-US

ASC-US, Most cases of ASC

Cytological features suggestive of LSIL

~4-5% of all abnormal Pap diagnoses

HPV +, ~ 50%

HSIL, 5-17%

9

Types of ASCUS

ASCUS, NOS

ASCUS in atrophy

ASCUS, atypical parakeratosis

Spectrum of lesions ranges from reactive to invasive carcinoma

Hoda. Cytojournal. 2008 Apr 24;5:10TP

ASCUS, NOS

ASC-USAtypical Parakeratosis

TP

ASCUS in Atrophy

SP

Koilocyte-like PKbi- or multinucleation

Steinman Acta Cytol. 2008;52:279

ASCUS FeaturesHormonal Rx Candida

Moriarty, Archiv Pathol Lab Med 2009;133:1272 SP

ASC-H mimics

10

ASCCP Guidelines 2012 ASC-US

Repeat Pap @ 6 & 12 moDetects 73% HSIL

Colposcopy

HPV-DNA testDetects 93% HSIL

Screening Guidelines for Prevention & Early Detection of Cervical Cancer, 2012

__________________________________

Updated, for Pap screening & in the management of adolescents & young

women with abnormal cytology

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 21-29 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

Saslow, CA Cancer J Clin 2012. Am J Clin Pathol 2012;137:516

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

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: DNAwithPapTest, 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)

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%

Stoler, AJCP, 2012;137:295. Datta, Ann Intern Med 2008;48:493

Prevalence in ASCUS decreases with age

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

Guo. Cancer Cytopathol. 2013;121:79

Histological Follow-up of HPV+ ASCUS

Mean age of HR HPV(+) ASCUS: 29

Negative ~50%

CIN 1 43.6%

CIN 2/3 5.1%

No impact of age or EC/TZS

Armah, Arch Pathol 2009;133:1426, Evans Ca Cyto 2006;106:1054

(-) biopsy indicates transient HPV infection

12

HPV (-), Cytology ASC-US

Risk of precancerous lesions is low

Recommend continued routine screening

Saslow. Am J Clin Pathol 2012;137:516; Hoda, USCAP abstract 2014

HPV (+), Cytology (-)

Repeat co-testing in 12 months

HPV 16/18 genotyping

Case #3________________________________

37-year-old woman

All prior Paps: Normal

Diagnosis: Atypical Squamous Cells, cannot exclude High-Grade Dysplasia, ASC-H

TPASC-H Definition,per Bethesda 2001

________________________________

Changes suggestive of HSIL,

but lacks definitive criteria

~5-10% of all ASC

0.3-0.6% 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

Colposcopy

28% may require > one bx

ASC-HSyncytia, disorganized cells

TPSP

Coarse nuclear chromatin is associated with HSIL, 84%

Gupta. Diagn Cytopathol. 2013;41:520

13

ASC-H, Hyperchromatic crowded groups

TP“Steep sides” & “straight edges”SP

ASC-H, Small “walnutty” atypical metaplastc cells

Histiocytes

IUD cell

Reactive

ASC-H mimics

MGH

ASC-H & Histological Correlation________________________________

HSIL 52%

CIN 2 20%

CIN 3 32%

Premenopausal 65%

Postmenopausal 35%

LSIL 23%

Benign 25%

Selvaggi. Diagn Cytopathol. 2013;41:943

ASC-US

~90% of ASC

HPV 16/18: 50%

HSIL 5–17%

HPV triage

ASC-H

~10% of ASCHPV 16/18: <85%HSIL 24–68%> colposcopy

Hoda & Hoda. Fundamentals of Pap Test Cytology, 2007

Case #4________________________________

28-year-old Woman

Routine Pap Test

14

TP

Low-Grade Squamous Intraepithelial Lesion, LSIL

TP

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

Colposcopy

LSIL MimicsLSIL Reactive

TP

LSIL versus Hormonal Changes (Glycogen)

SP

Hoda. Diagn Cytopathol. 2013;41:257

Untreated LSIL:

~90% of CIN1 lesions regress within 2 yrs, specially in young

~15–25% may progress to CIN 2/3

CIN 1: Natural History________________________________

Cell blocks from residual LBP vial may detectCIN 2 lesions

Catteau. Acta Cytol. 2012;56:247

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

Waldstrom. Cancer Cytopathol. 2013;121:136

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%

CINtec + CINtec in LSIL

Borderline Category between LSIL & HSIL

LSIL, Cannot Exclude HSIL (LSIL-H)

The discrepancy rate between low- and high-grade lesions ranges from 9.8 to 15%

TBS, 2008

LSIL, cannot exclude HSIL (LSIL-H)

Elsheikh Cancer Cyto 2006;108:277

Atypical keratinized cells

LSIL-H

HSIL-like cells with unequivocal LSIL

0.15% - 0.35% Paps

Risk of: hrHPV & histologic CIN 2/3

LSIL-H 90% 30%

HSIL 96% 70%

LSIL 80% 13%

ASC-H 54% 17%

Baron. Am J Clin Pathol. 2014;141:239Walavalkar. Cancer Cytopathol. 2014;122:123

Case #5________________________________

Routine Pap in a 37-year-old

with

Intra-Uterine Device

16

High-Grade Squamous Intraepithelial Lesion ~HSIL

TP

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

HSIL Criteria, Bethesda 2001

Syncytia N:C Metaplastic-type cells

TP TP

Nuclei: coarse chromatin, grooves, irregular

HSIL, Syncytia

HSILSP

Small “walnutty” cells, Nuclei 2-3x interm. cell nucleus, Look in empty spaces Bare nuclei

TPHSIL

17

CIN2 versus CIN3

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

HSIL Involving Endocervical glands

SP

Features HSIL in EC glands AIS

_________________________________________

Central cell polarity - +

Overlapping + -

Nucleoli micro prominent

‘Feathering’ - +

p63 + -

Apoptosis -/+ +

Mitoses -/+ +

High N:C + +

p16 overexpressed + +

Kir. J Cytol. 2012;29:121; Wood Diag Cytopathol 2007;35:12 AIS vs HSIL in ECG

25% to 75% of cases have both

HSIL Small cell ca

TTF1 +Hoda, USCAP Poster 2012

39%

31%

10%

20%

Most Common Pap Dx Preceding HSIL on Bx

44.5% of Pap Preceding HSIL on Bx were diagnosed as HSIL

18

Missed HSIL cases: Small, pale cells

Khalbuss. Cytojournal. 2013 Aug 30;10

Differential Diagnosis

HSILImmature Squamous

Metaplasia

Atrophy HSIL, Syncytia

Basal Cell Sheets in Atrophy Mimic HSIL

TP

TP

LUS vs HSIL

HSIL

Benign Endometrial Cells Mimic HSIL

TP

EMC

SP

Hoda. Diagn Cytopathol. 2013;41:257

TP

IUD vs HSIL

Pinto, Acta Cytol. 2012;56:109. Ge, Acta Cytol. 2012;56:55

19

False-Positive for HSIL

Atrophic vaginitis

Repair

HSV

Crothers. Arch Pathol Lab Med. 2014;138:613

HSVrepairAV

ASCCP Guidelines 2006 HSIL

Colposcopy

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

Katki. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S78

Role of HPV Test in HSIL________________________________

Segunda parte del Curso Corto

Case 6________________________________

48-year-old womanroutine Pap test

ThinPrep

------

TP

20

Squamous carcinoma

TP SP

Differential Diagnosis

TP

Repair Non-keratinizing sq. ca

Fiber cell

Squamous Cell Ca, Keratinizing

Tadpole cell

Background in atrophy mimics Squamous Ca

Selvaggi Diagn Cyto 2002:27:362

TP

ASC-US ASC-H

LSILHSIL

Squamous Ca

29% increase in incidence in recent years

Dr. Pap

21

Case #7________________________________________________

64-year-old, postmenopausal

Prior Paps: negative

History: Breast cancer, 2004

Medications: Estrogen 5 years until 2002

ThinPrep

Cellular, mucin, architecture variability

Loose sheets,

mucinous cytoplasm

Nuclei, palisaded, lobate,

irregular, nucleoli

Strips, columnar cells & dark oval nuclei

Cytological Diagnosis__________________________________________________

Atypical Glandular Cellsof Endocervical Origin

AGC, EC

AGC: Initial Workup_____________________________________________________________________________________

ECC: Dissolved on processingEMBx: Endometrial polyp

HPV: Negative

22

AGC: Subsequent Workup_____________________________________________________________________________________

6 mos later

Cervical Cone

Minimal Deviation Adenoca of Cervix, MDADepth of invasion >7mm

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

Zardo, Acta Cytol 2009;53:558

Glandular CellsBethesda 2001

____________________________________________________________________________________

Atypical

Endocervical cells, nos

Endometrial cells, nos

Glandular cells, nos

Atypical

Endocervical cells, favor neoplastic

Glandular cells, favor neoplastic cells

AIS, Adenocarcinoma

AGC, EC- Follow-up studies_____________________________________________________________________________________

Benign 20% - 40% Squamous neoplasia 40% - 80% Neoplasia 0% - 10% EMCa is the most common malignancy

Ajit. Acta Cytol. 2013;57:45; Cohen. AJCP 2010;133:799

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

23

Usual type

Mucinous

Endocervical, intestinal, signet-ring

Endometrioid

Clear cell

Unusual types

MDA

Mesonephric

Serous

Villoglandular papillary adenocarcinoma

Invasive Endocervical Ca, Classification_____________________________________________________________________________________

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%

Li, Int J Gynecol Obstet 2010,110:89. Renshaw, Arch Pathol Lab Med 2004;128:153

Diagnostic Sensitivity for MDA 33%

ADCA on Pap: False-Negative Rate

_____________________________________________________________________________________

AIS 12%

ADCA 9%

HSIL 4.6%

squamous ca 3.3%

Li, Int J Gyne Obstet 2010,110:89. Kalir, Int J Gynecol Pathol 2005;24:399

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

___________________________________________________________________

MDA

CS - MDA

DDX- Benign EC

Khalbuss. Cytojournal. 2013 Aug 30;10

Large sheet

“Golden yellow” mucin in Paps

Hashi, Diagn Cytopathol 2008;36:535. Hata, Diagn Cytopathol 2002;27:80

PAS & HIK1083 + Not seen on LBP

Conventional Pink mucin in normal EC

MDA LEGH

24

Review of Histologically-proven MDA from 1975-2009

Precise pre-op diagnosis:

by Pap & bx remains difficult

IHC: CEA, Ki67, AB/PAS, HIK1083 & SMA

Tsuji, Histopathol 2011;59:55. Li, Int J Gynecol Obstet 2010,110:89

_____________________________________________________________________Treatment of MDA

Radical hysterectomy

_____________________________________________________________

MDAon Liquid-Based Preps

Diagnostic dilemma Golden-yellow mucin not seen HPV test & p16 are negative

Case #8_____________________________________________________________________________________

36-year-old, Pap, ThinPrep

Previous Paps: Negative

Clinically: Ectropion

ThinPrep

Clean background, HCG & sheets 

ThinPrep

Palisading 

Nuclei dark, oval, chromocenters, high N/C 

25

Cytological Diagnosis_____________________________________________________________________________________

Adenoca In Situ of Endocervix

AIS

Colposcopy, Cervical & Endometrial Biopsies Followed

Biopsies: Negative

Ectropion LEGH

__________________________________________________________

Cone: AIS

Repeat Pap 4 weeks later: AIS

At transformation zone Precursor of adenocarcinoma Symptomatic: 3% Incidence 0.61/100,000 Multifocal-multicentric in 50% Rx: Cone, Hysterectomy

_______________________________________________________________________________

AISBasics

_____________________________________________________________________________________

Zardo, Acta Cytol 2009;53:558

ECA ~43, AIS ~37 AIS > ECA: ~13 yrs CIS to Squamous ca: ~18 yrs AIS usually adjacent to ECA HPV: 18 & 16

________________________________________________________________________

AIS & ECARelationship

_____________________________________________________________________________________

Zardo, Acta Cytol 2009;53:558. Plaxe, Gynecol Oncol 1999;75:55

AIS 55-70% ECA 72% HSIL 73% Squamous ca 75%

AIS on PapSensitivity

_____________________________________________________________________________________

Xing. Cancer Cyto. 2014;122:8; Hoda. Diagn Cytopathol. 2011;39:730

Cell blocks may detect a significantly more endocervical or endometrial adenocarcinoma

compared with the ThinPrep alone (36% vs 8%)

26

AIS 12% ECA 9% HSIL 4.6% Squamous ca 3.3%

AIS on PapFalse-negative

_____________________________________________________________________________________

AIS not detectable by Pap if TZ spared, 54% vs. 25%, p = 0.036

Kalir, Int J Gynecol Pathol 2005;24:399

Clean background hyperchromatic crowded groups Columnar monomorphous cells Nuclei crowded, molded Stippled chromatin Nucleoli Feathering, rosettes, strips Apoptosis & mitosis_____________________________________________________________________________________

AISDiagnostic Criteria

_____________________________________________________________________________________

Hoda & Hoda. Fundamentals of Pap Test Cytology, 2007.

ThinPrep

Hyperchromatic crowded groups & sheets

Clean background Columnar, crowded cells

Rosettes, Nuclei, nucleoli Apoptosis & Mitosis

Conventional

• Best criterion, PPV 73%

• Feathering & HPV+ =

glandular neoplasia

“Feathering” in Glandular Neoplasia

Rabelo‐Santos, Cytopathol 2008;19:34

Tubal metaplasia Lower uterine segment Reactive endocervical cells Invasive ECA HSIL involving endocervical glands

AISDifferential Diagnosis

_____________________________________________________________________________________

Hoda & Hoda, Fundamentals of Pap Test Cytology, Springer, 2007

27

Tubal metapla

SurePath

Reactive EC LUS

AIS

ThinPrep

ECA AIS

ThinPrep ThinPrep

AIS vs HSIL in ECG

25% to 75% of cases have both

HPV test: Glandular LesionsHPV, 16 & 18

_____________________________________________________________________________________

Sensitivity for AIS 86% - 100% Sensitivity for ECA 85% - 94% Specificity & NPV 100% & 97%

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

___________________________________________________________________

Minimal difference

in endocervical neoplasia

in conventional & LBP

AIS onLiquid-Based Preps

28

17-year-old

Two previous normal Paps

Pap, ThinPrep

Case 9_________________________________________________________

TeenagerRoutine Pap

ThinPrep

mitosissmooth-contoured papillary

featheringThinPrep

Reported as Negative,

Reactive Endocervical Cells

Cytological Diagnosis_________________________________________________________

ECA Villoglandular Type

Biopsy performed

Hoda. Diagn Cytopathol. 2010;38:633

ECA with Villoglandular ComponentHPV-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

29

Hypercellular Flat sheets

DiathesisAIS-Like

SurePath

Nuclei dark, nucleoli; Cytoplasm scant

Key Feature of Invasion NucleoliThinPrep

Post-cone changes AIS Endometrial adenoca Squamous cell ca Metastatic adenoca

Adenoca of EndocervixDifferential Diagnosis

_____________________________________________________________________________________

Wood, Diagn Cytopathol 2007;35:12Hong, Acta Cytol 2001;45:163

Post-cone: small uniform dark nuclei

ThinPrep

ThinPrep

SurePath

ThinPrepConventional

ECA in Conventional, SP & TP

Bai, Diagn Cytopathol 2000;23:19  Belsley, Diagn Cytopathol 2008;36:232

General Management

Depends on the stage

TAH or conization for early stages

Radical hysterectomy, pelvic lymphadenectomy, chemo & radiation for later stages

___________________________________________________________

30

2012 Cervical Cancer Screening Guidelines

ACS/ACOG/ASCCP

21 yrs: Routine screening starts

21-29 yrs: every 3-yrs

30-65 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

Ma. Cancer Cytopathol. 2013;121:432

Characteristic appearance HPV-status unreliable Cytology: key role in detection

EC CaOn Liquid-Based Prep

Case 10

______________________________________________________

65-year-old

Vaginal Bleeding

SurePath

Granular Background

Diagnosis______________________________________________________

Endometrial Adenocarcinoma

Clinical Presentation of Endometrial Carcinoma

Bleeding

Watery discharge

Increase in size of uterus

Pain

31

Endometrial Adenocarcinoma on Pap______________________________________________________

Sensitivity <50% Specificity <97% +Pap in 25% of asymptomatic patients

+Pap = higher grade, larger, thicker >5mm

Norimatsu. Diagn Cyto. 2013;4:120; Watanabe Cancer Cytopathol 2009;117:254

Liquid-Based Preparation Better

Cytology of Endometrial Adenocarcinoma______________________________________________________

Single cells, tight clusters

Variable nuclear size

Hyperchromatic nuclei

Nucleoli

Polarity, less with increase in grade

Diathesis in 33%

ThinPrep-Sensitivity:73%, Specificity:100% & Positive Predictive Value:100% in endometrial carcinoma

Zhou. Diagn Cytopathol. 2013;41:408

Watery Diathesis inEndometrial Carcinoma

Selvaggi, Diagn Cytopathol 2005;33:162

ThinPrepConventional

“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 ThinPrep, 36% vs 8%

Zing. Cancer Cytopathol. 2014;122:8; Nambu. Diagn Cytopathol. 2012;40:701

Papillary Serous Carcinoma

Mixed Mullerian Tumor

Clear CellCarcinomaEndometriod Carcinoma

32

Endocervical Carcinoma Endometrial Carcinoma

3-dimension clusters rounded > cytoplasm watery diathesis

2-dimension clusters columnar < cytoplasm bloody diathesis

7% associated with Actinomyces

TP

Use of IUD reduces risk of endometrial carcinoma Cellular immunity is protective?

Castellsagué. Lancet Oncol. 2011;12:1023

Accurate Diagnosis by“Pattern Recognition”

Lesson

_____________________________________________

Case 11________________________________

26-Year-Old Post-Coital Bleeding

Pap Test, ThinPrep

ThinPrep

33

Hypercellular Single & Clustered Cells

Dirty Necrosis & Malignant Cells “Cigar” Nuclei

Diagnosis:Metastatic Colonic Carcinoma

Metastases in Paps_______________________________

Rare, <1% Rarely a primary event

Usually primary is known Symptom: bleeding

Khalbuss. Cytojournal. 2013;10:17 Hoda. Acta Cytol. 2004;48:586

34

Direct Extension, Usually Rectum

Childs Recurrent colorectal carcinoma detected by routine cervicovaginal pap testing. Low Genit Tract Dis 2005;9:236

From Peritoneum, via Fallopian Tube

Gupta Extrauterine malignancies. Role of pap smearsin diagnosis and management. Acta Cytol 1999;43:806

Metastasis, Distant Sites

Mousavi Isolated cervical metastasis of breast cancer: a case report and literature review. J Low Genit Tract Dis 2007;11:276

Most Common Metastases in Paps_______________________________

Breast Colon

Urinary bladderEndometrium

Ovary

Otsuka. Br J Cancer. 2013;109:603. Hoda. Diagn Cyto. 2005;33:58

Psammoma Bodies_______________________________________________

Spherical bodies, Calcified concentrically

Neoplastic: Papillary carcinoma

Non-neoplastic: Endosalpingiosis

Calcified IUD debris mimics psammoma

Meisels

Gupta. Cytomorphological features of extra-genital metastases in SurePath™ cervical liquid-based cytology: a series of 8 cases. Cytopathology. 2013;24:123

Metastatic Merkel Cell Carcinoma

Hoda , Acta Cytol 2004;48:586

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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…”

Rebecca Skloot: The Immortal Life of Henrietta Lacks

“…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 HeLaCells”

Rebecca Skloot: The Immortal Life of Henrietta Lacks