Cervix-cytology
Last revised 28 May 2008
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Table of contents - Cervix-cytology
Primary references, images needed, general, Pap, liquid based, Diff-Quik, Bethesda system
Normal cells / nonneoplastic findings: air drying artifact, Barr body, blue blobs, cilia, cornflakes, degeneration, endocervical cells, endometrial cells, eosinophils, exodus, histiocytes, hyperkeratosis, immature squamous metaplasia, insect parts, intermediate squamous cells, lower uterine segment endometrium, lymphocytes, male cells, maturation index, navicular cells, neutrophils, parabasal cells, parakeratosis, PM cells, post-hysterectomy, psammoma bodies, repair, small blue cells, squamous cells, squamous metaplasia, superficial squamous cells, syncytium, transitional metaplasia, tumor diathesis, unsatisfactory specimen
Inflammation/parasites: actinomycosis, bacterial vaginosis, Candida, Chagas’ disease, chlamydia, chronic cervicitis, CMV, Enterobius, granuloma inguinale, granulomas, herpes, Lactobacillus, Leptothrix, Schistosomiasis, syphilis, Trichomonas, tuberculosis, Wucheria
Benign/non-neoplastic lesions: general, adenomyoma, adenosis, Arias-Stella reaction, atrophy, atypical polypoid adenomyoma, decidual reaction, endocervical polyp, endometrial polyp, endometriosis, endosalpingiosis, florid ectopy, leiomyoma, lobular endocervical hyperplasia, mesonephric rests, mesonephric hyperplasia, microglandular hyperplasia, myofibroblastoma, squamous papilloma
Atypia / Premalignant / preinvasive lesions: HPV, condyloma, atypical glandular cells, atypical repair, atypical reserve cell hyperplasia, atypical squamous cells, chemotherapy effect, radiation atypia, SIL-general, LSIL/CIN I, HSIL/CIN II, HSIL/CINIII, adenocarcinoma in situ, Paget's disease, stratified mucin producing intraepithelial lesions
Carcinoma: squamous cell carcinoma, microinvasive SCC, adenocarcinoma, microinvasive adenocarcinoma, adenoid basal, adenoid cystic, adenosquamous, clear cell, endometrial, glassy cell, lymphoepithelioma-like, mesonephric adenocarcinoma, metastases to cervix, minimal deviation adenocarcinoma, serous papillary adenocarcinoma, small cell, urothelial, verrucous, villoglandular papillary adenocarcinoma, warty
Sarcoma/lymphoma/other: sarcoma-general, Ewing’s sarcoma/PNET, granulocytic sarcoma, leiomyosarcoma, lymphoma, malignant mixed mullerian tumor, melanoma, plasmacytoma, reticulum cell sarcoma, rhabdomyosarcoma, stromal sarcoma
Go to Cervix chapter/outline
American Journal of Clinical Pathology (AJCP), August 1975 to February 2006
American Journal of Surgical Pathology (AJSP), March 1977 to January 2006
Archives of Pathology and Laboratory Medicine (Archives), June 1976 to January 2006
Human Pathology (Hum Path), May 1974 to January 2006
Modern Pathology (Mod Path), March 1988 to January 2006
DeMay: The Pap Test: Exfoliative Gynecologic Cytology (1st Ed); ASCP, 2005
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); Mosby, 2004
Solomon: The Bethesda System for Reporting Cervical Cytology (2nd Ed); Springer, 2005
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Websites: Histopathology and cytopathology of the Uterine Cervix-Digital Atlas, American Society of Cytopathology-National Cancer Institute Atlas, University of Texas
Journal search terms: cervix, cervicovaginal, smear, cytology
Please refer to these primary references for additional discussion and images
Images needed (for cervical cytology)
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Cytology images are particularly needed for these cervix lesions:
Normal cells / nonneoplastic findings: cornflakes, eosinophils, male cells, PM cells
Inflammation / parasites: Chagas’ disease, Enterobius, syphilis,
Benign/non-neoplastic: adenomyoma of endocervical type, adenosis, Arias-Stella reaction, atypical polypoid adenomyoma, decidual reaction, endocervical polyp, endometrial polyp, endosalpingiosis, leiomyoma, mesonephric rests, mesonephric hyperplasia, myofibroblastoma, squamous papilloma
Atypia/pre-malignant/preinvasive: immature condyloma, atypical repair, atypical reserve cell hyperplasia, chemotherapy effect, keratinizing SIL
Carcinoma: papillary squamotransitional, microinvasive squamous cell carcinoma, signet ring adenocarcinoma, microinvasive adenocarcinoma, adenoid basal, adenoid cystic, adenosquamous, clear cell, lymphoepithelioma-like, minimal deviation adenocarcinoma, serous papillary adenocarcinoma, verrucous, warty (condylomatous)
Sarcoma/lymphoma/other: Ewing’s sarcoma/PNET, granulocytic sarcoma, leiomyosarcoma, rhabdomyosarcoma
Cytology-general
The most successful application of clinical cytology is diagnosing cervical abnormalities before they develop into invasive cervical carcinoma
Used for screening and follow-up of cervical carcinoma, particularly squamous carcinoma
Cytology smears are sensitive to abnormalities, although there is variable interpretation on any particular smear; the most important factor is to detect an abnormality and to start an appropriate management plan
Specimen should be obtained and prepared by trained individuals
False negative tests are often due to poor quality specimens and inadequate sampling (Mod Path 1992;5:337), erroneous interpretation and error by screeners
Endocervical sampling should be performed to confirm that the entire transition zone was sampled, although many studies show no association between absence of endocervical cells / transition zone and a higher risk of squamous lesions on subsequent smears (AJCP 2001;115:851, Acta Cytol 1986;30:258, Cancer 2001;93:237, Lancet 1991;337:265)
For endometrial carcinoma, pap smear is only 50% sensitive; 60% with cervical scrapings, 75% with vaginal pool material; thus, pap smears are not appropriate for screening endometrial abnormalities
Liquid based cytology performed by cytocentrifugation is reported to be efficient and inexpensive (CytoJournal 2005;2:15); is associated with higher rates of LSIL and lower ratios of atypical squamous cells/LSIL (Archives 2004;128:1224, Archives 2003;127:200)
HPV testing may be more sensitive than cytology in detecting HSIL (Br J Cancer 2005;93:575)
HPV testing is an integral part of management of ASCUS (atypical squamous cells of uncertain significance), ASC-H (atypical squamous cells, cannot exclude HSIL) and to evaluate AGUS (atypical glandular cells, Am J Obstet Gynecol 2005;193:559)
Recent study of simultaneous FISH for HPV E6 and E7 mRNA had 83% sensitivity and 91% sensitivity for high grade SIL compared with Pap smear in 231 liquid based cytology samples (AJCP 2005;123:716)
References: screening guidelines from Brigham and Women’s Hospital, Boston, Massachusetts (USA)
Alcohol dried; better for nuclear detail
Stains ribosomes blue green, particularly in parabasal cells, mesothelial cells and metaplastic squamous cells
Stains metabolically inactive cells pink, such as superficial cells
Stains keratinized cells or thick specimens orange (benign or malignant)
Fix quickly and stain carefully; air dried smears are inadequate
Images: smearing and slide preparation; procedure for staining
Cytology images: conventional smears-examples of good cellularity
References: Wikipedia
Head of spatula, where cells are lodged, is broken off into small glass vial containing preservative fluid, or rinsed directly into preservative fluid
Sample is sent to lab, then spun and treated to remove mucus, pus or other obscuring material
Random sample of remaining cells is taken and deposited onto a slide
Reduces number of inadequate smears and need for repeat smears
Thin-Prep appears to be superior to convention Pap test in detecting SIL (Archives 2003;127:200, Archives 1999;123:817, Mod Path 1998;11:837)
Approved by US Food and Drug Administration in 1997
Major companies are Cytyc (ThinPath) and TriPath Imaging (SurePath)
Can use residual material to prepare cell blocks and for immunohistochemistry (Cancer 2004;102:142)
Images: smearing and slide preparation
Cytology images: examples of liquid based samples
Diff-Quik stain in cervical cytology
An air dried, Giemsa-type stain
Better for background material or to assess adequacy of endocervical smears to detect C. trachomatis (J Clin Microbiol 1996;34:2590)
Used for fine needle aspirates, not for cervical smears
Bethesda System 2001 for Cervicovaginal Cytology reporting
Based on workshop held in April/May 2001 at National Cancer Institute (NCI reference, JAMA 2002;287:2140)
By 2003, was implemented by 85% of labs participating in College of American Pathologists’ Interlaboratory Comparison Program in Cervicovaginal Cytology (Archives 2004;128:1224)
Specimen type
Indicate conventional smear (Pap smear), liquid based preparation or other preparation (describe)
Specimen adequacy
Satisfactory for evaluation (describe presence or absence of endocervical/transformation zone component and all other quality indicators, such as partially obscuring blood, inflammation, etc.)
Assessment of specimen adequacy (satisfactory and unsatisfactory):
1 - Adequate number of squamous cells (conventional smear should have 8000-12000 cells, liquid-based preparation should have 5000 cells)
2 -The presence or absence of endocervical cells should be reported; an adequate number of endocervical cells (at least 10 well-preserved endocervical or metaplastic cells) confirms sampling of transition zone
3 - Specimen with more than 75% of cells obscured by inflammation and bacteria is unsatisfactory (however, should still report presence of abnormal cells)
Unsatisfactory for evaluation (indicate reason)
Specimen rejected/not processed (indicate reason)
Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality (indicate reason)
Interpretation/result
Negative for Intraepithelial Lesion or Malignancy (NILM)
Organisms
• Trichomonas vaginalis
• Fungal organisms morphologically consistent with Candida species
• Shift in flora suggestive of bacterial vaginosis
• Bacteria morphologically consistent with Actinomyces species
• Cellular changes associated with Herpes simplex virus
Other non-neoplastic findings (optional to report, list is not inclusive)
• Reactive cellular changes associated with:
- inflammation (includes typical repair)
- irradiation
- Intrauterine contraceptive device (IUD)
• Glandular cells status post hysterectomy
• Atrophy
Other
• Endometrial cells (in a woman greater than or equal to 40 years of age; specify if “negative for squamous intraepithelial lesion”)
Epithelial Cell Abnormalities
SQUAMOUS CELL
• Atypical squamous cells
- of undetermined significance (ASC-US)
- cannot exclude HSIL (ASC-H)
• Low grade squamous intraepithelial lesion (LSIL)
- encompassing HPV/mild dysplasia/CIN I
• High grade squamous intraepithelial lesion (HSIL)
- encompassing: moderate and severe dysplasia/CIN2/CIN3/CIS
- with features suspicious for invasion (if invasion suspected)
• Squamous cell carcinoma
GLANDULAR CELL
• Atypical
- endocervical cells (NOS or specify in comment)
- endometrial cells (NOS or specify in comment)
- glandular cells (NOS or specify in comment)
• Atypical
- endocervical cells, favor neoplastic
- glandular cells, favor neoplastic
• Endocervical Adenocarcinoma in situ
• Adenocarcinoma
- endocervical
- endometrial
- extrauterine
- not otherwise specified (NOS)
OTHER MALIGNANT NEOPLASMS (Specify)
ANCILLARY TESTING: Describe briefly the test method(s) and report the result so that it is easily understood by the clinician
AUTOMATED REVIEW: If case is examined by automated device, specify the device and result
EDUCATIONAL NOTES/SUGGESTIONS: If provided, should be concise and consistent with clinical guidelines published by professional organizations
References: details from IARC/WHO
Normal cells / non-neoplastic findings
Air drying artifact-cervical cytology
Due to delay in immersion in alcohol fixative
More common on conventional than liquid based smears
Specimen is unsatisfactory if more than 75% of cells show air drying; if less extensive, may be mentioned as a quality indicator
May cause discrepant diagnosis of LSIL or less for HSIL smears (Cancer 2002;96:218)
Associated with ASCUS in perimenopausal women (Cancer 2001;93:100)
Cytology: cells are degenerated, eosinophilic, enlarged and lightly stained; nuclei are pale, flattened and lack chromatin detail
Cytology images: apparently normal #1; #2; atrophy in post-menopausal woman; ASCUS #1; #2; LSIL; HSIL
Inactive X chromosome, present on nuclear margin, formed by telomere association (Proc Natl Acad Sci USA 1991;88:6191)
Identified by Dr. Murray Barr
Images: drawing; in squamous epithelial cell #1; #2; #3; crumbled up X chromosome in neutrophil #1; #2; other
References: Barr body
Represent condensed mucus, degenerated bare nuclei, precipitating hematoxylin
In post-menopausal women, represent parabasal/intermediate squamous cells with various degree of degeneration (Acta Cytol 2000;44:547)
Cytology: dark blue, rounded, amorphous masses
Cytology images: liquid based cytology with amorphous basophilic material #1; #2; #3; page 14, figure 1.7b (PDF file)
Almost always implies a benign lesion, such as tubal metaplasia, which may simulate adenocarcinoma in situ
May be associated with endometrioid type of minimal deviation adenocarcinoma of cervix (AJSP 1993;17:660)
Note that the presence of single cells with cilia is insufficient to diagnose tubal metaplasia, according to Bethesda 2001
Case report: ciliated adenocarcinoma of cervix (Acta Cytol 2005;49:187)
Cytology images: various images
Also called “brown artifact”, cornflaking
Distinctive appearance is due to evaporation of xylene before cover slipping, with deposition of air on superficial squamous cells
More common on conventional than liquid based preparations
Cytology images: page 20, figure 1.19a (PDF file)
References: National Association of Cytologists
Degeneration-cervical cytology
Occasionally called retroplastic change
Due to delay in transfer of cells to the slide
Also associated with inflammation or atrophy
More common on conventional than liquid based preparations
Cytology: cytoplasm is lost and moth eaten with vacuolization; chromatin is clumped, hazy, smudged or indistinct; chromatin rim has variable thickness and irregular contours, but no sharp angles of malignancy
Cytology images: degenerated cells #1; #2; degenerated parabasal cells-page 14, figure 1.7a (PDF file)
Endocervical cells-cervical cytology
Most effective device for collection appears to be cytobrush and extended tip spatula (Cochrane Database Syst Rev 2000;CD001036)
Presence of endocervical cells indicates that the upper limit of transformation zone was included, so collection is adequate
Cytology: usually columnar cells (2 mm) with vacuolated or granular cytoplasm, prominent cell borders, basal nuclei with fine granular chromatin and occasional nucleoli; honeycomb appearance en face; ciliated if tubal metaplasia
Cytology images (conventional): various images #1; #2-secretory cells; #3-ciliated; large cluster of cells #1; #2; #3; #4; en face #1; #2; #3; tubal metaplasia #1; #2; #3; reactive #1; #2; #3
Cytology images (liquid based): various images; en face; tubal metaplasia #1; #2; endocervical cells (SurePath)
Endometrial cells-cervical cytology
Reports of associated endometrial pathology in postmenopausal women with benign endometrial cells at pap smear (AJCP 2005;123:571, Diagn Cytopathol 2001;45:153) versus no association (Cancer 2005;105:207, Diagn Cytopathol 2001;25:235)
Most associated carcinomas are in women age 45+ years (AJCP 2005;124:834)
May also be due to hormone replacement therapy (Obstet Gynecol 2002;100:445) or tamoxifen
Resemble histiocytes; easier to identify if in clusters
Cytology images: various images #1; #2; #3; #4; endometrial stromal cells #1; #2; IUD related changes
Cytology images: contributed by Dr. Carmen Luz, Spain - Thin Prep of normal endometrial group-postmenstrual cycle
May be associated with parasites (Diagn Cytopathol 2003;29:167); also allergic reactions to chemicals, medications or sperm
Cytology: pink granular cytoplasm and binucleated
Images: peripheral blood; ankle biopsy for blastomycosis; nasal mucosa in allergic rhinitis
Cytology: menstrual endometrium with central core of densely packed stroma surrounded by degenerated and partially necrotic cells; histiocytes, neutrophils and degenerated cells in a dirty background
During menstrual cycle days 6 to 10 (proliferative phase or exodus phase), the endometrial cells are present in a “double contour” pattern with glandular epithelial cells surrounding the stromal cells in the center
Cytology images: various images of endometrial cells, including during menstruation; page 38-PDF file
Clinical history is more predictive of endometrial pathology than presence of histiocytes (Acta Cytol 2003;47:135, Acta Cytol 2003;47:762)
Cytology: larger than neutrophils, vacuolated or frothy cytoplasm (scant to moderate), round to reniform (bean shaped) nuclei, central or eccentric, chromatin fine to coarse but uniformly distributed, nucleoli variable
Epithelioid histiocytes: usually in aggregates
Multinucleated histiocytes: randomly arranged nuclei with granular chromatin
Cytology images: various images #1; #2; histiocytes #1; #2; #3; multinucleated #1; #2
Hyperkeratosis / keratinization-cervical cytology
top
Extensive hyperkeratosis is patches of anucleated squamous
cells with irregular, angulated edges present in 5+ low power fields on a
conventional smear; for liquid based preparations, in 3+ low power fields
An abnormal finding; may be associated with malignancy (0-2%) or HPV/dysplasia (17-22%) (Acta Cytol 2003;47:749, Am J Obstet Gynecol 2002;187:997); present in 70% of Thin-Prep specimens of invasive squamous cell carcinoma (Diagn Cytopathol 2002;26:1)
SIL cases are difficult to grade (AJCP 2001;115:80); pathology report of prominent atypical keratosis should state “cannot exclude high grade SIL”
Cytology images: various images #1; #2; #3; conventional smear #1; #2; liquid based smear #1; #2; #3
DD: SIL (hyperkeratosis is not marked, irregular chromatin clumping, irregular nuclear membranes, disorganized growth pattern, Diagn Cytopathol 1997;17:447)
Immature squamous metaplasia-cervical cytology
Associated with endocervical cells
Cytology: cells are parabasal or basal type; have dense, dark cytoplasm that is reduced in quantity, increased N/C ratio, uniform oval nuclei; often seen in loose aggregates in “jigsaw” configuration; resembles reserve cell hyperplasia
Cytology images: various images; atypical metaplastic squamous cells with increased N/C ratio and nuclear enlargement-biopsy revealed immature squamous metaplasia
Insect parts-cervical cytology
Carpet beetle larval parts may be a contaminant of cotton swabs, wooden swabs or tampons (Acta Cytol 1985;29:345)
Cytology images: carpet beetle parts
References: Archives 2005;129:809, carpet beetle information
Intermediate squamous cells-cervical cytology
Predominate in luteal phase
Nuclear grooves are not associated with inflammation, but are increased in HSIL (Acta Cytol 2003;47:421)
Cytology: cytoplasm is polygonal, transparent, basophilic, flat/thin (due to keratin); nucleus is about the size of a red blood cell, is vesicular, round/oval; nuclear texture and size is reference for dysplasia; may see cytolysis / dirty background, Doderlein bacilli
Cytology images: various images (some are intermediate cells); intermediate cells #1; #2; #3; #4; #5
Lower uterine segment endometrium-cervical cytology
Associated with use of endocervical brush (pushed too high into cervical os) and post-cone biopsies (Diagn Cytopathol 1995;12:263)
May mimic atypical glandular lesions, endometriosis, HSIL or be considered “inconclusive”
Does not warrant reporting according to Bethesda 2001 if seen in absence of exfoliated endometrial cells
Cytology: large groups with gland openings, branched glands, nuclear palisading within fragments; often endometrial stroma and smaller fragments that are densely cellular with nuclear palisading
Cytology images: long tubular branching glands in monomorphic stroma; glandular cells of endometrial origin
References: