Anogenital Cytology: Charles D. Sturgis, MD

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Anogenital Cytology: Charles D. Sturgis, MD
Anogenital Cytology:
Recent Developments & Clinical Correlates
Perspectives from a Cytopathologist
Charles D. Sturgis, M.D.
Cytopathologist, CellNetix Pathology & Laboratories
Medical Director of Microbiology Laboratory, Providence Regional Medical
Center Everett
Staff Pathologist, Swedish Hospital Edmonds
Staff Pathologist, The Everett Clinic
[email protected]
425-530-8184
Washington, U.S.A.
1
Disclosures for Dr. Sturgis
I am a partner in CellNetix Pathology & Laboratories, a physician
owned group of pathologists. While you
are obviously under no obligation, we hope that
you might consider a professional relationship
with us. I can be contacted at
[email protected]
or at 425-530-8184.
I will be touching on a few commercially available tests / testing
platforms in this talk. I have no financial ties to or
ownership stake in any of these entities.
2
Program Overview

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Brief CellNetix Introduction.
Historical Perspectives on Pap testing.
Bethesda and Cytomorphology Correlates.
Anal cancer stats/trends and sexual demographics.
“LAST” update.
HPV Basics.
Cigarette smoking and HPV mediated diseases.
Liquid Based Cytology.
Automated Screening / Diagnostics.
Ancillary Testing.
HPV Genotyping.
3
What is CellNetix?

Is it a high fiber breakfast cereal? No

Is it trademark chemotherapeutic agent? No
Is it a group of pathology professionals? Yes
(A PLLC and an LLC with a consolidated laboratory)
------------------------------------------------------------------------------------
CellNetix was founded in 2005 through the fusion of three
practices:

Seattle (Swedish), Everett (Providence), and Olympia (Providence).

Now also Edmonds (Swedish Edmonds), Aberdeen (Grays Harbor),
North Seattle (Northwest), Centralia (Providence), Palmer Alaska (Mat
4
Colleen Dewhurst
Tony & Emmy award winning Canadian actress
Died of cervical cancer in 1991 at age of 67.
Eva Peron
Jade Goody
Argentinian Political Leader
Died of cervical cancer in 1952 at age of 33.
British “Reality” TV star of Big Brother
Died of cervical cancer in 2009 at age of 28.
5
Historical Perspectives
 In the 1940s, cervical cancer was the #1 cause of
cancer death for American women.
 Between 1955 and 1992, the incidence of cervical
cancer in the United States decreased by 74%.
 Today, carcinoma of the uterine cervix ranks 14th
in frequency in American women.
6
Historical Perspectives
Dr. George N. Papanicolaou
(1883-1962)
The Papanicolaou smear, a simple test based upon microscopic
study of cells exfoliated from the uterine cervix, was introduced
in the 1940s and 50s and became widely used in the 1960s and 70s.
This is the most effective cancer screening test ever developed.
7
Historical Perspectives

In 1996, the U.S. FDA approved the use of the first liquid based,
thin layer slide preparation as an alternative to conventional Pap.

ALTS trial 1996-2000. Prospective trial for 5,000 women with ASCUS/
LSIL from Univ Alabama, Univ Pittsburgh, Univ Oklahoma, & Univ
Washington. Patients followed every six months for two years.
Three triage arms of ALTS:
1. Immediate colposcopy.
2. Repeat cytology with colpo if cytology of HGSIL.
3. HPV test and repeat cytology with colpo if HR HPV positive or HGSIL.
More than 70 papers have been published from data of ALTS group:
One main finding being that HPV testing is sensitive in detecting
underlying precancerous lesions among women with ASCUS.
HPV testing was 96-percent sensitive - that is, identified 96% of women
with ASCUS who had a precancerous lesion
Combining cytology with HR HPV testing has a negative predictive value
for CIN 2+ of 99-100%.
D. Solomon, M. Schiffman, R. Tarone for the ALTS Group, Journal of the National Cancer Institute, Feb 21, 2001:92(12):293-299).
8
Historical Perspectives
 Bethesda revised in 2001.
 Unified interpretive categories
based upon proven and
repeatable morphologic
features.
 Consistent defined
and translatable terminology.
 Meaningful correlation of
interpretations with outcomes
allowing for prognostication
and management based
upon a probabilistic approach.
 Incorporated data and results
from early parts of ALTS.
9
Bethesda and Cytomorphologic Correlates
Colposcopic Refresher
10
Bethesda and Cytomorphologic Correlates
Atypical Squamous Cells:
 ASC-US (undetermined significance), morphologic differential LGSIL, approx 10% CIN II or
greater on bx.
 ASC-H (cannot exclude HSIL), morphologic differential HGSIL, 30 to 40% CIN II or
greater on bx.
 DOES NOT REPRESENT A SINGLE BIOLOGIC ENTITY.
Epithelial Cell Abnormality, Squamous:
 LSIL (low grade squamous intraepithelial lesion), correlates to HPV change and CIN 1.
 HSIL (high grade squamous intraepithelial lesion), correlates to CIN 2 and CIN 3.
 Squamous carcinoma.
Epithelial Cell Abnormality, Glandular:
 Atypical endocervical cells NOS.
 Atypical endometrial cells NOS.
 Atypical glandular cells NOS.
 Atypical endocervical cells favor neoplastic.
 Atypical glandular cells favor neoplastic.
 Endocervical adenocarcinoma in situ.
 Adenocarcinoma, endocervical, endometrial, extrauterine, NOS.
Other Malignant Neoplasms:
 Small cell carcinoma, sarcomas, etc…
11
Bethesda and Cytomorphologic Correlates
LGSIL
Delicate acetowhite epithelium irregularly
extending from transformation zone.
Well circumscribed anterior lip lesion with dense
acetowhite change, mosaic periphery,
HGSIL
punctations, increased iIntercapillary distances,
extends into canal.
Carcinoma
Fungating cauliflower-like mass lesion with
erythema, necrosis and hemorrhage.
12
Bethesda and Cytomorphologic Correlates
“Older linear” paradigm for
individuals developing anogenital
dysplasia / carcinoma.
“Newer nonlinear/bidirectional”
paradigm with
modern concepts of HPV
mediated carcinogenesis
13
Bethesda and Cytomorphologic Correlates
14
Bethesda and Cytomorphologic Correlates
LGSIL
ASC-US
HGSIL
ASC-H
15
Most high grade dysplasias
and carcinomas of the cervix
arise at the transformation zone
(this is a “migratory”
squamo-columnar junction).
16
The anal SCJ is nearly
always “internal” within
the anal canal and like
cervical cancers is also
generally the site of
origin for high grade
dysplasias and carcinomas.
17
Let's Talk About Sex May 18, 2012
To Pap or Not to Pap: Update on Anal Pap Smears
Scott Itano, M.D.
Swedish Family Medicine – Seattle, WA
http://www.swedish.org/For-Health-Professionals/CME/Archives---2012-Conferences/Let-s-Talk-about-Sex/Online-Syllabus/Files/1130Itano
EPIDEMIOLOGY
The age-adjusted incidence rate was 1.7 per 100,000 men and women per year.
These rates are based on cases diagnosed in 2005-2009 from 18 SEER geographic areas.
Based on rates from 2007-2009, 0.18% of men and women born today
will be diagnosed with cancer of the anus at some time during their lifetime.
This number can also be expressed as:
1 in 568 men and women will be diagnosed with cancer
of the anus during their lifetime.
National Cancer Institute. Surveillance Epidemiology and End Results (2012).
18
Epidemiology of Anal Cancers:
Incidence trends are increasing in both men and women.
19
Anal Canal HPV Infection in Men Who Have Sex with Men
The majority of “Gay” men have anal HPV.
All HPV
HR HPV
20
Histopathologic outcomes and clinical correlations for
high-risk patients screened with anal cytology.
Zhao C, et al Acta Cytologica 2012;56(1):62-7. doi: 10.1159/000331431. Epub 2012 Jan 4.
Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. [email protected]
OBJECTIVE: Anal cytologic testing is being increasingly used as a preventive screening test
in high-risk populations. We document anal cytology results, correlating HIV test results, and
histopathologic follow-up outcomes from a large integrated health system which recently
implemented anal screening.
STUDY DESIGN: Anal Pap tests between May 2007 and August 2009 were studied and
correlated with HIV test histories and follow-up histopathologic diagnoses.
RESULTS: 688 anal cytologic tests were identified with 7.4% reported as unsatisfactory;
72% of anal cytologic tests were abnormal; 91% of patients were HIV positive. The HIV-positive
rate and likelihood of high viral load were both significantly greater among patients with
abnormal anal cytology than among patients with negative anal cytology, but did not vary
significantly among patients with different categories of abnormal anal cytology. For 459
patients with abnormal anal cytology, 198 had anal biopsies. For patients with abnormal anal
cytology findings of ASC-US, LSIL, ASC-H, and HSIL, histopathologic intraepithelial neoplasia
(AIN)2/3 or 2/3+ diagnoses were established in 46.5, 56.6, 65, and 80.8%, respectively.
CONCLUSIONS: Patients with any level of abnormal anal cytology result are at significant
risk of the presence of histopathologically verifiable high-grade anal intraepithelial lesions.
21
Gwen Welles
Farrah Fawcett
Star of Robert Altman’s hit film Nashville, 1975
Died of anal cancer at age 42 in 1993.
Star of Television’s Charlie’s Angels, 1976-1980
Died of anal cancer at age 62 in 2009.
22
Anoscopic Images
To Pap or Not to Pap: Update on Anal Pap Smears - Scott Itano, M.D.
Swedish Medical Center, Seattle, Family Medicine, 2012
23
57 squamous carcinomas
of the anus over 10 years
at PRMCE.
748 squamous carcinomas
of the anus over 10 years
in Washington.
Tables courtesy of Lynda Oehlsen, Senior Admin Assist, PRCP
43 squamous carcinomas
of the cervix over 10 years
at PRMCE.
984 squamous carcinomas
of the cervix over 10 years
in Washington.
24
Majority of anal cancer patients are female.
(approximately 2-3:1)
25
Anus
In Washington State,
average age for
anal cancer is
about 10 years
older than
average age for
cervical cancer.
Keep in mind:
Cervix “screened”
Anus not “screened”
Also keep in mind:
Vaccination may
impact future
generations.
Cervix
26
Pelvic Anatomy
27
How many sexually active American women
between the ages of 18 and 40
engage in anal intercourse?
I asked this question of several female coworkers
including physicians, nurses, technologist, and lab clerical staff.
Responses ranged from 5% to 60%.
The real answer is…
28
National Survey of Sexual Health & Behavior
(NSSHB from Indiana University, 2010)
20 - 25% of sexually active American women
women between 20 & 40 years of age have
engaged in receptive penile – anal
intercourse in the last year
29
Would it not
make sense
to think of all
warts in the
anogenital region
as one
disease process?
Vulvar Warts
Perianal Warts
Prevention Training Center at the University of Washington/ UW HSCER Slide Bank – CDC STD
Prevention – Gordon D. Davis, MD, Cincinnati STD/HIV Prevention Training Center, Centers for
Disease Control and Prevention Public Health Image Library
They are all
caused by
the same strains
of the same DNA
virus – HPV.
30
Penile Condyloma
Fitzpatrick’s Dermatology in General Medicine
7th Ed., Wolff K, et all McGraw-Hill, Inc
Genital Human Papillomavirus Infection in Men.
Partridge JM, Koutsky LA. Lancent Infect Dis. 2006 Jan;6(1):21-31.
Department of Epidemiology, University of Washington HPV Research Group, University of Washington, Seattle, WA 98103, USA
31
http://dermatlas.med.jhmi.edu/image/Genital_warts_2_040606
32
The Lower Anogenital Squamous Terminology Standardization
Project for HPV-Associated Lesions: Background and Consensus
Recommendations from the College of American Pathologists
and the American Society for Colposcopy and Cervical Pathology
Archives of Pathology and Laboratory Medicine Volume 136, Issue 10 (October 2012)
T Darragh; T Colgan; J Cox; D Heller; M Henry; R Luff; T McCalmont; R Nayar; J Palefsky; M Stoler; E Wilkinson;
R Zaino; D Wilbur; For members of the LAST Project Working Groups
Abstract
The terminology for human papillomavirus (HPV)–associated squamous lesions of the lower anogenital tract has a long
history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV
biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites.
The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses
available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous
Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy
and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and
developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster
implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a
consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations
including professional societies and government agencies. Recommendations were finalized and voted on at the consensus
meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated
squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and
detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for
disseminating and monitoring recommendation implementation in the practicing community was also developed. The
implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve
accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.
33
“LAST” Project General Principles and Working Groups
34
WG2
A unified histopathologic nomenclature with a single set of diagnostic terms is recommended
For all HPV-associated preinvasive squamous lesions of the LAT.
The recommended terminology for HPV-associated squamous lesions of the LAT is:
low-grade squamous intraepithelial lesion (LSIL) and
high-grade squamous intraepithelial lesion (HSIL)
These may be further classified by the applicable –IN subcategorization. Thus, for an –IN 3 lesion:
cervix = CIN 3, vagina = VaIN 3, vulva = VIN 3, anus = AIN 3, perianus = PAIN 3, and penis = PeIN 3.)
Concern was expressed that using the same terminology for cytology and histomorphology would
not allow for distinction as to whether the diagnosis was associated with a cytologic or
histologic specimen. On a written pathology report, the specimen type is clearly stated, so this
confusion is minimized. However, in short-hand verbal communication, it may be important to
designate reports as associated with cytology or histology specimens. The option of adding the
specific –IN terminology with the basic 2-tiered classification would also help to identify these
samples as histopathology.
The LAST Standardization Project for HPV Associated Lesions Consensus Recommendations
Darragh, T.M., et al, Archives of Pathology & Laboratory Medicine – Vol 136, October 2012
35
The similarity of morphology between LAT sites and between sexes is shown. Each is
an example of a precancerous HSIL. If reviewed without knowledge of biopsy site or
sex of the patient, they would be impossible to distinguish from one another.
A, CIN 3 (female); B, AIN 3 (female); C, AIN 3 (male); D, PeIN 3 (male).
The LAST Standardization Project for HPV Associated Lesions Consensus Recommendations
Darragh, T.M., et al, Archives of Pathology & Laboratory Medicine – Vol 136, October 2012
36
Cervix.—It is thought that all SCCs of the cervix are attributable to HPV. There are abundant
data that early invasive squamous carcinoma (SCC) of the cervix can safely be treated
conservatively. Historically, a variety of terms, including microinvasive carcinoma, have been
used to label this group. Criteria for defining patients amenable to conservative management
have changed over the years.
Vagina.—Vaginal cancers are rare. Approximately 40% to 60% of SCCs of the vagina are
attributable to HPV. In addition, vaginal squamous carcinomas are, in general, not amenable to
local resection.
Vulva.—. Approximately 40% to 50% of SCCs of the vulva are attributable to HPV.
WG3
Penis.—Cancers of the penis are rare in the United States. Approximately 40% of SCCs
Recommendations
of the penis are attributable to HPV.
Anal Canal.—Approximately 90% to 93% of anal canal SCC is attributable to HPV.
Historically, abdominoperineal resection was the primary management for anal canal cancer. In
the 1980s, primary surgical therapy was supplanted by combined modality therapy which has
achieved superior survival rates and reduced recurrence rates while preserving the anal sphincter.
Perianus.—The proportion of SCC of the perianus attributable to HPV are different between
women and men, with 80% of female and 29% of male perianal cancers associated with HPV.
The perianus is currently defined as the region extending 5 cm from the anal opening or verge.
This region overlaps anatomically with the vulvar perineum.
The LAST Standardization Project for HPV Associated Lesions Consensus Recommendations
Darragh, T.M., et al, Archives of Pathology & Laboratory Medicine – Vol 136, October 2012
37
Anal
Transformation Zone
Cervical
Transformation Zone
38
“LAST” Biomarkers
WG4 evaluated data associated with the following biomarkers:
p16, Ki-67, ProExC, L1, HPV 16/18mRNA, telomerase/TERC and HPV genotyping.
Only p16, a biomarker reflective of E6/E7 driven cell proliferation had sufficient
evidence on which to make recommendations regarding use in LAT squamous lesions.
WG4
Some cases of HSIL, especially in the zone of immature metaplasia
where the epithelium may be thin, can be diagnostically problematic.
In this cervical biopsy (A), the differential diagnosis includes
inflamed immature squamous metaplasia and HSIL. Strong diffuse
block-positive p16 staining (B) strongly favors the interpretation of
this biopsy as precancer (HSIL).
A, High power, H&E. B, High power, p16.
Some immature squamous metaplastic lesions can be
hyperplastic rather than thin (A, contrast with Figure 15A).
In this case, the cervical epithelium mimics bladder mucosa
with somewhat elongate nuclei and some nuclear grooves
(transitional metaplasia). Note the absence of mitotic figures
and relative nuclear uniformity. B, The near total absence
of p16 reactivity strongly supports the interpretation that
this is a HSIL mimic rather than precancer.
A, High power, H&E. B, High power, p16.
39
Pathologic diagnoses using p16 and potential clinical management options for cervical biopsies.
A, Use of p16 to evaluate the differential diagnosis of HSIL versus a mimic, such as immature squamous metaplasia
and atrophy.
B, Use of p16 to evaluate morphologic CIN 2. The choice of clinical management for HSIL depends on the entire
clinical scenario including patient's age, colposcopic findings, and biopsy diagnosis. Management options include
excisional therapy (cold knife conization, LEEP), ablative therapy (cryotherapy, laser vaporization), and close
observation, as during pregnancy.
Modified with permission. Courtesy of Philip E. Castle.
The LAST Standardization Project for HPV Associated Lesions Consensus Recommendations
Darragh, T.M., et al, Archives of Pathology & Laboratory Medicine – Vol 136, October 2012
40
HPV Basics
H&E stained histologic section of cervix.
Classical koilocytes in Papanicolaou
stained cervicovaginal cytology.
HPV first ultrastructurally
reported in 1949.
Virion consists of:
icosohedral (polyhedron with
20 triangular faces) protein
coat (capsid) that encloses viral
genome of circular double
stranded DNA.
Electron micrograph of HPV (NIH).
These viruses are small
and non-enveloped.
41
HPV Basics
42
Gene Function:
E1
DNA-dependent ATPase, ATP dependent helicase: allow unwinding of the viral
genome and act as an elongation factor for DNA replication.
E2
Responsible for recognition and binding of origin of replication. Exists in two forms:
full length (transcriptional transactivator) and truncated (transcriptional repressor).
The ratio of these found in the heterotrimeric complex formed before complexing
with E1 regulates transcription of viral genome.
E4
Late Expression: C terminal binds intermediate filament, allowing release of viruslike particles. Also involved in transformation of host cell by deregulation of host
cell mitogenic signaling pathway.
E5
Obstruction of growth suppression mechanisms: e.g. EGF receptor; activation of
mitogenic signaling pathways via transcription factors: c-Jun and c-Fos (important
in ubiquitin pathway degradation of p53 complex by E6). Inactivation of p21 (p53
induced expression halts cell cycle until DNA is proof-read for mutations).
E6
E6 Transformation of host cell by binding p53 tumour suppressor protein.
E7
Transforming protein, binds to pRB/p107.
L1
Major capsid protein: can form virus-like particles.
L2
Minor capsid protein: possible DNA packaging protein.
43
HPV Basics
 Human papillomavirus (HPV) affects both females and males.
 HPV transmission can happen with any kind of sexual, genital
contact with someone who has HPV—intercourse isn't
necessary.
 Many people who have HPV don't even know it, since
the virus often has no signs or symptoms. That means
HPV transmission can happen without anyone knowing it.
 There are about 6 million new cases of genital HPV in the
United States each year. It's estimated that 74% of them occur
in 15- to 24-year-olds.
44
HPV Basics
Why do some people infected with HPV progress to
carcinoma but most do not?
Fair answer: I/we don’t know.
Variables include but not necessarily limited to:
 Strains / subtypes involved
 Host cellular and humoral immunity
(coinfections, medications, autoimmunity)
 Host mechanisms for specific tumor suppressor
genes
 Comorbidities such as tobacco use, nutrition and
concurrent diseases
45
There are more than 100 “types” of HPV.
Not all cause anogenital cancers.
Oncogenic risk
HPV types
Associated
lesions
Established
Low Risk
6, 11, 13, 40,
42-44, 54, 61, 70,
72, 81 and
CP6108
26, 53, 66, 68, 73
and 82
Condyloma
acuminatum
LSIL (10-20%)
Probably High
Risk
LSIL, HSIL, AIS,
carcinoma
Established High 16, 18, 31, 33, 35, LSIL, HSIL, AIS,
Risk
39, 45, 51, 52, 56, carcinoma
58 and 59
46
HPV-Mediated Anogenital Carcinogenesis
Episomes are closed circular DNA molecules.
Woodman et al, Nat Rev Cancer 2007;7:11-22
47
Relationship Between Cigarette Smoking and HPV Types
16 and 18 DNA Load.
Xi LF, Koutsky LA, Castle PE, Edelstein ZR, Meyers C, Ho J, Schiffman M.
Source: Cancer Epidemiol Biomarkers Prev. 2009 Dec;18(12):3490-6.
Department of Pathology, University of Washington, Seattle, USA. [email protected]
BACKGROUND: Although cigarette smoking has been associated with increased human papilloma
virus (HPV) detection, its impact on HPV DNA load is unknown.
METHODS: The study subjects were women who were positive for HPV16 and/or HPV18 at
enrollment into the Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous
Intraepithelial Lesion Triage Study. Assessments of exposure to smoke and sexual behavior were
based on self-report. Viral genome copies per nanogram of cellular DNA were measured by
multiplex real-time PCR. Linear or logistic regression models were used to assess the relationship
between cigarette smoking and baseline viral load.
RESULTS: Of the 1,050 women (752 with HPV16, 258 with HPV18, and 40 with both HPV16 and HPV18),
452 (43.0%) were current smokers and 101 (9.6%) were former smokers at enrollment. The baseline
viral load was statistically significantly greater for current compared with never smokers (P = 0.03 for
HPV16; P = 0.02 for HPV18) but not for former smokers. Among current smokers, neither HPV16
nor HPV18 DNA load seemed to vary appreciably by age at smoking initiation, smoking intensity, or
smoking duration. The results remained similar when the analysis of smoking-related HPV16 DNA
load was restricted to women without detectable cervical abnormality.
CONCLUSION: Higher baseline HPV16 and HPV18 DNA load was associated with status as
a current but not former smoker. A lack of dose-response relationship between cigarette smoking
and viral load may indicate a low threshold for the effect of smoking on HPV DNA load
48
HPV Basics
Why is cervicovaginal screening for HPV mediated
disease precursors so important?
These numbers speak for themselves:
Five Year Disease-Free
Survival
Local (%)
Regional (%)
Distant (%)
Targeted Cancers:
Breast
98.1
83.1
26
Colorectal
90.4
68.1
9.8
Ovarian
93.1
69
29.6
Malignant Melanoma
99
64.9
15.3
Cervical
92
55.5
14.6
49
Liquid Based Cytology
There are currently two FDA
approved liquid based
cervicovaginal cytology products
available:
Hologic’s ThinPrep Pap Test
&
BD SurePath Pap Test
The ThinPrep product is the
preferred specimen collection
system at CellNetix.
50
Liquid Based Cytology
Why Liquid Based Cytology Anyway?
 Many studies have shown increases in sensitivity and positive predictive values
for cervicovaginal cytology with liquid based cytology when compared to
traditional smears.
Liquid-based cytology: evaluation of effectiveness, cost-effectiveness, and
application to present practice. Women's Clinic, Health Services, University of
California, Santa Barbara, CA, USA. Natl Compr Canc Netw 2004 Nov;2(6):597-611. Cox JT.
15 "direct-to vial” studies
Aggregate sensitivity for the CP was 71.5% and for LBC was 80.1%.
 Alternatively, a recent meta-analysis of all studies from 1991 to 2007 comparing
liquid based cytology to conventional smears (authors from Belgium) concluded
that “liquid based cervical cytology is neither more sensitive or more specific for
detection of HGSIL compared with the conventional Pap test.”
Arbyn M, et al. Obstet Gynecol. 2008 Jan;111(1):167-177.
 As a reader of the literature, and a consumer of the products, I feel that the truth
lies somewhere in the middle.
51
Liquid Based Cytology
Reasons to Consider Other than Sensitivity:
Uniformity of preparation.
Monolayer.
Potential to remove debris and inflammation.
Additional testing performed from vial (HPV, GC, CT).
Potential use for immunocytochemistry/
immunohistochemisty.
Automated screening / diagnostics.
Increased laboratory productivity.
Lower unsatisfactory rates.
52
Liquid Based Cytology
Hologic ThinPrep
53
Liquid Based Cytology
BD SurePath
1. Debris
2. Enriched
cell pellet
Centrifugation through density reagent
Resuspension
Transfer to settling chamber
Sedimentation by gravity
54
Reading pap smears is a bit like bird watching….
55
The ThinPrep Imager (Cytyc)
Dual Review
Entire slide screened by a
automated proprietary computer
system.
Selected 28 fields reviewed by
cytotechnologist.
56
BD Focal Point Slide Profiler
A.
Slides with scores below the primary threshold can be archived with no further review
B.
Slides with scores above the primary threshold are reviewed by cytotechnologists
C.
Slides with scores above the QC threshold are re-screened by cytotechnologists
57
Why ThinPrep is the Preferred
Product at CellNetix
Excellent sensitivity and negative predictive value for ThinPrep samples.
Ease of interpretation (monolayer appearance) of slides resulting in
reproducibility.
FDA approval of the Digene Hybrid Capture 2 (HC2) HPV assay on
ThinPrep samples (not on SurePath).
Extensive literature and clinical outcomes studies based upon ThinPrep
and HC2 HPV including but not limited to all papers published on the
ALTS data set.
Automation that incorporates human decision making / slide reading with
location guided microscopic screening, benefiting the patient by
ensuring that all slides are viewed by both "man and machine".
58
BD Technical Bulletin from June 2012:
“Use of SurePath sample medium has not been approved by FDA
for use with HCII tests.”
“SurePath sample medium may under certain circumstances provide
false negative results.”
“False negative results could lead to inappropriate patient management
and potentially compromise patient safety.”
59
2012 Cervical Screening Guidelines
(ACS, ASCCP, ASCP).
Cervical cancer screening (testing) should begin at age 21.
Women under age 21 should not be tested.
Women between ages 21 and 29 should have a Pap test every 3 years.
HPV DNA testing should not be used in this age group unless needed after an abnormal Pap.
Women between the ages of 30 and 65 should have a Pap test plus an HPV DNA test
(“co-test”) every 5 years. (Pap testing alone every 3 years is an acceptable alternative).
Women over age 65 who have had regular cervical cancer testing with normal results should
not be tested for cervical cancer. Once testing is stopped, it should not be started again.
Women with a history of a serious cervical pre-cancer should continue to be tested for at least
20 years after that diagnosis, even if testing continues past age 65.
A woman who has had her cervix/uterus removed for reasons not related to cervical cancer
and who has no history of cervical cancer or serious pre-cancer should not be tested.
A woman who has been vaccinated against HPV should follow the screening
recommendations for her age group.
Some women – because of their history – may need a different screening schedule.
Saslow, et al. American Journal of Clinical Pathology 2012; April, 137:516-542.
60
The goal of
anal screening
is to prevent
cancers.
Until consensus
guidelines
become
available, who
and how
should we
screen?
61
Obtaining Specimens for Anal Cytology:
Obtaining an adequate anal cytology specimen involves the following steps:
1. Moisten a Dacron swab with water. It is important to use a Dacron swab,
not a cotton swab, because cells cling to cotton swawbs.
2. Insert the swab 4 to 5 cm (2 inches) (the length of the patient’s 5th finger)
into the anal canal and proceed through the dentate line and
transitional zone between the squamous and columnar epithelia.
3. Rotate the swab firmly with lateral pressure while slowly inserting
and withdrawing in a tight spiral motion for 15 to 20 seconds.
4. Place the swab in liquid-based medium (ThinPrep CytoLyt solution) and
swish the swab vigorously for 15 to 20 seconds.
5. Dispose of the swab; cap and label the specimen jar.
Anal cancer and Screening Guidelines for Human Papillomavirus in Men
Ortoski JR DO and Kell CS PhD, J Am Osteopath Assoc, March 2011 111:S35
From the departments of family medicine and microbiology, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania.
62
Symptoms of Anal/Perianal HPV Infection Include:
Bleeding from the anus or rectum
Pain or pressure in the area around the anus
Itching or discharge from the anus
A lump near the anus
Most people asymptomatic!
Who should have an anal Pap smear? There are no set guidelines for screenings.
Anyone who has receptive anal sex should have an anal Pap smear once a year.
Anyone with a history of anal warts should have anal Pap smear once a year.
It is recommended that men having sex with men should have the procedure each year.
Those who are HIV positive are at particular risk for anal cancer and should be screened every year.
Is an anal Pap smear effective? The anal Pap smear’s effectiveness is similar to the cervical Pap smear.
Both are good at early detection of abnormal cells but not at predicting future changes.
That’s why it’s so important to have a doctor that specializes in the diagnosis, follow-up testing and
treatment of HPV and anal issues.
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63
Prevalence of anal cytological abnormalities
in women with positive cervical cytology.
Calore EE, et al, Diagn Cytopathol, 2011 May;39(5):323-7. doi: 10.1002/dc.21386.
Pathology Department, Emílio Ribas Infectology Institute, Sao Paulo, Brazil. [email protected]
The objective of this study was to estimate the prevalence of cytological abnormalities
of the anal mucosa in women with positive cervical cytology, but without macroscopic
anal lesion. Ultimately we postulated if the anal mucosa may be a reservoir of HPV, which
would allow the reinfection of cervix. Forty-nine patients with abnormal cervical cytology were
selected for this work. In a period not exceeding one week of collecting cervix cytology, two
swab specimens of the anal canal were also collected. Women diagnosed with cervical HSIL
by Pap smear were referred for colposcopy with biopsy of the lesions, to confirm the cytologic
diagnosis and ablation of the lesion. We demonstrated a high prevalence of anal squamous
intraepithelial lesions in patients with cervical squamous intraepithelial lesions (29 of the total
of 49 patients = 59.2%). Of the 20 cases of cervical LSIL, 11 (55%) had abnormal anal
cytology. Of the 26 cases with cervical HSIL, 16 (61.5%) had abnormal anal cytology. So,
there was a discrete higher prevalence of abnormal anal cytology in cases of high-grade
cervical squamous lesions (cervical HSIL). These results help to support the hypothesis that
the anal mucosa is a reservoir of HPV, which can be a source of re-infection for the cervix…
64
Consider Anal Cytology Screening in:
Men who have / have had sex with men (annually).
Those with HIV (annually).
Those 30 years of age and older with current or prior history of any
anal sexually transmitted diseases (annually).
Women 30 years of age and older who:
Engage/d in anal intercourse (same interval as cervical Pap and consider DNA cotest).
Ever had HSIL or higher on Cervical Pap (same interval as cervical Pap).
----------------------------------------------------------------------------------------------------------------------------------------------
Other risk groups in which anal screening may be pertinent:
Women with cervical LSIL.
Women with positive cervical high risk HPV DNA testing.
Current smokers.
Patients with altered immunity other than HIV.
Autoimmune / collagen vascular disorders.
Recipients of organ transplantation.
Patients with family history of anal cancers?
Consider testing patients with two or three of these.
-------------------------------------------------------------------------------------------------------------Remember that patients with a mass or symptoms of anal cancer may need
a diagnostic evaluation rather than or in addition to a screening test.65
Summary
Women's Cancers, Cancer
Estimates (US)
Estimated 2007
Incidence
Estimated 2007
Mortality
678,060
270,100
178,480
40,460
Colorectal
74,630
26,180
Ovarian
22,430
15,280
Malignant Melanoma
26,030
2,890
Cervical
11,150
3,670
All Sites
Cancers:
Breast
Dr. Papanicolaou’s simple test has saved countless lives, and the
medical community has done a wonderful job, but people still
die from this “preventable” disease.
66
Summary
Who is diagnosed with cervical
cancer in Washington today?
Women who are not screened
or are not screened regularly.
Images below are from a 42F with an Everett address, hysterectomy 01-21-09.
She presented to a local doc 11-04-08 with bleeding.
She had never before had a Pap test.
Pap
Bx
Hyst
67
Dr. Boudousquie
Swedish Edmonds
Dr. Fidda
Providence Olympia
Dr. Isacson
Seattle Swedish
Dr. Jordan
Seattle Swedish
Dr. Kahn
Providence Everett
Dr. McDonagh
Northwest Seattle
Dr. Patton
Northwest Seattle
Dr. Perez-Reyes
Seattle Swedish
Dr. Pizer
Seattle Swedish
Dr. Sturgis
Providence Everett
Dr. Kawamoto
Swedish Edmonds
Dr. Tickman
Seattle Swedish
The CellNetix Cytology Team
68