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Gynecologic Cytology
Fadi W. Abdul‐Karim, MD MEd
Department of Anatomic Pathology
Vice Chair Education RT‐PLMI
Professor of Pathology
Cleveland Clinic . Cleveland Ohio
Disclosure of Relevant Financial Relationships
USCAP requires that all planners (Education Committee) in a position to
influence or control the content of CME disclose any relevant financial
relationship WITH COMMERCIAL INTERESTS which they or their
spouse/partner have, or have had, within the past 12 months, which relates to
the content of this educational activity and creates a conflict of interest. Dr. Abdul‐Karim has nothing to disclose.
Normal Maturation of Squamous Epithelium
• Cells become bigger
• Cells change from round to oval to polygonal
• Cytoplasm volume increases
• Long axis of nucleus changes from perpendicular to parallel
• Nuclear size decreases
• Nuclear size decreases,cytoplasm increases, N/C ratiodecreases
• Mitotic activity only inparabasal cells
• Cyanophilic basal cells mature to pink/orange staining cells
“Maturation Index”
: :
Parabasal cells : Intermediate cells : Superficial cells
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Normal Squamous cells “Maturation Index”
• Mature pattern = estrogenic stimulation– MI = 50 S : 50 I : 0 PB
• Atrophic pattern = absence of estrogen– MI = 0 S : 0-50 I : 50-100 PB
• Intermediate pattern– Mostly I cells present
Immature Squamous Epithelium
Composed throughout the entire thickness of basal and/or parabasal cells.
–At the transformation zone where it is called squamous metaplasia
–Squamous epithelial atrophy due to low estrogen state
Squamous Metaplasia at TZ
Typical Location of SQ‐ Col Junction
Old and new TZ Age related changes
Squamous Metaplasia
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TBS: Non‐neoplastic Cellular Variations
Squamous Metaplasia
Criteria:
• Squamous metaplastic cells which show a range of cytoplasmic differentiation.
• From immature parabasal‐like cells to those that approximate the appearance of differentiated intermediate/superficial cells . The mean nuclear area is larger than that of the intermediate cell and similar to the parabasal cell at 50 μm 2 .
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ECN: 40um2
MCN:50um2
ICN:35um2
Immature Squamous Metaplasia
• The Cytoplasm– Parabasal shaped– Homogeneous/Muddy consistency
– Amphophilic color– Sharp cytoplasmic borders– Punched out vacuoles– Cobblestone pattern
• Spider cells can be seen especially in CP:– Strange pulled out shapes– Most commonly seen in conventional smears
Maturing Squamous Metaplasia
Lower N/C ratio, with finely granular chromatin +/‐small nucleoli. With maturation lose muddy cytoplasm and nuclei begin to look more like IC.
Endocervical/TZ component: 10 well‐preserved endocervical or squamous metaplastic cells singly or in clusters TZ Component: Atrophy
• Parabasal type cells may mimic squamous metaplasia and small columnar cells
• Degenerated cells in mucus and parabasal type cells should not be counted in assessing transformation zone sampling.
• In atrophic Paps: laboratory may elect to make a comment about the difficulty of assessing the transformation zone component.
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“Maturation Index”
: :
Parabasal cells : Intermediate cells : Superficial cells
Atrophic pattern = absence of estrogenMI = 0 S : 0-50 I : 50-100 PB
Atrophy: Parabasal Cells
Highly variable changes reflecting the differing levels of hormonal support
Squamous atrophy: Clinical setting associated with
low estrogen state/decrease of hormonal support
• Pre‐menarche: Newborn female will initially have a cellular profile of maternal hormones. Maternal hormones wane, to an to an atrophic pattern. The atrophic pattern is gradually replaced by an IC pattern several years before menarche. Cyclic changes about 18 mo. before menstruation.
• Post‐partum: 75% of lactating women and one out of three non‐lactating women had atrophic smears at six weeks postpartum
• Post‐menopause• Premature ovarian failure• Turner syndrome• Status post bilateral Lactation• High dose progestin therapy • Radiation therapy, chemotherapy, hysterectomy or trachelectomy for invasive cervical cancer
Atrophic Squamous Epithelium
Atrophy: Early to Deep
Atrophy: Dispersed parabasal‐type cells and small clusters
Mild hyperchromasia and tend to have more elongated nuclei. Uniform chromatin distribution and regular nuclear contours
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Atrophy: Degenerated parabasal cells Blue blobs
Degenerated or algophilic cells or eosinophilic parabasal cells with smudgy nuclei and pyknosis “pseudo parakeratosis”“
Blue blobs: Globular collections of basophilic amorphous material; degenerated parabasal cells or inspissated mucus.
Atrophy: Stripped nuclei (Should elicit search for classic intact HSIL).
HSIL: Larger than ICN. Nuclear features of HSIL.
Atrophy: Autolysis and degenerative changes. Uniform in size. Possible nucleoli.
Atrophy: Generalized Nuclear Enlargement
PM Cells: Squamous cells with enlarged smooth, bland nuclei in perimenopausal women; No hyperchromasia and no membrane irregularities
• 15% of ASC‐US, but should be interpreted as NILM
• Threshold of ASC should be raised in 40 – 55 year‐olds
• Cause is unknownRef: Am J Clin Pathol 2005;124:58‐61
PM: “Atypia” vs. ASC
PM “Atypia”
Enlarged poorly preserved PB cells w/o hyperchromasia or pleomorphism
Small orangeophilic cells
Field effect
No mitoses
Hyperchromatic crowded groups
ASC
Excessively large PB cells with pleomorphism and hyperchromasia
Atypical PK
Focal changes
Mitoses
Hyperchromatic crowded groups
ASC: Atypia in Atrophy
• NILM‐ PM: Mild bland nuclear enlargement is a common cause for ASC over
utilization. Changes of mild nuclear enlargement without significant hyperchromasia or nuclear irregularity “postmenopausal atypia” and are usually HPV‐neg. NILM: In the absence of definitive abnormalities, especially in women who have no prior history of squamous cell abnormalities or do not have a prior positive hrHPV test.
• ASC‐US: Atrophic smears showing nuclear enlargement with hyperchromasia
that fall short of a definitive interpretation of SIL.
• ASC‐H: Occasionally and especially in high risk population, if it raises concern for HSIL
– The interpretation of HSIL may be difficult to make in an atrophic background because of the lack of maturity (and hence high nuclear to cytoplasmic ratio) of the parabasal cells.
In low‐risk scenarios, it may be prudent to categorize such atypias as ASC‐US rather than ASC‐H and allow adjunctive hrHPV testing to determine downstream management which may avoid overtreatment.
ASC in Atrophy • Reporting of atrophic changes is variable and poorly
reproducible . Atypical cellular changes associated with atrophy warrant an interpretation of atypical squamous cells (ASC). Although cytology should be judged on its own morphologic merits:
• A patient is more likely to have significant disease:– In face of a history of previous cervical abnormality – Prior positive high‐risk HPV test. – Women using DepoProvera are at increased risk
because they are young and sexually active
In addition, atrophy may coexist with dysplasia or neoplasia, and the diffusely increased nuclear to cytoplasmic ratio of background parabasal/basal squamous cells can make identification of true abnormalities more challenging. As such, these cases should be reviewed with care.
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ASC in PM
In atrophic smears
Bethesda: nuclear enlargement, hyperchromasia, irregularities in nuclear contour or chromatin or marked cellular pleomorphism (tadpole or spindle cells)
Atypical Squamous Cells (ASC)
• Nuclear enlargement 2.5-3x size of I cell ( in Atrophy ? 3-4 times).
• Slight increase N:C
• +/- variation in nuclear size and shape
• +/- binucleation, mild hyperchromasia
• Even chromatin, smooth nuclear contour
• Features suggestive of SIL
ASC in Atrophy: ASC‐US Atypical Squamous Cells in Atrophy: ASC‐US
ASC‐H in Atrophy
ASC‐H in PM is usually associated with NILM or LSIL on follow up. HSIL in 6% while 22% in premenopausal. In low risk patients consider ASC‐US to allow for HPV testing.Saad RS. Et al. ASC‐H in PM and Perimenopausal women. Am J. Clin Pathol 2006;126:381‐388 and TBS
LSIL in Atrophy
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LSIL Management Atrophy: Flat sheets of parabasal cells
Monolayer sheets of parabasal‐like cells with preserved nuclear polarity and little nuclear overlap in individual focal planes. Nuclei may be elongated /streaming in one direction with uniform chromatin distribution
Atrophy: Relatively large syncytial aggregates
Parallel streaming arrangements of nuclei in cells that have indistinct relatively dense cyanophilic cytoplasm
Atrophy: Hyperchromatic Crowded Groups
Atrophy: Transitional Cell Metaplasia Atrophy: Transitional Cell Metaplasia
Multilayered groups of cohesive PB with streaming spindled, grooved nuclei with tapered ends, wrinkled contours and perinuclear haloes.
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Hyperchromatic Crowded Group: Grouping that impede the ability to see the individual cells in the middle
• Benign
– Endocervical cells
– Endometrial cells
– LUS
–Atrophy– Tubal metaplasia
– Micro‐glandular hyperplasia
– Clusters of inflammatory cells
• Neoplastic/Preneoplastic
– (ASC‐H)
– HSIL
– AIS
– Squamous cell carcinoma
• Adenocarcinomas
HSIL: Cytologic Criteria
Single cells
– Discrete parabasal‐like cells
– High N/C ratio
– Irregular nuclear contours
– Marked hyperchromasia
– Coarse chromatin
Groups of cells– hyperchromatic crowded groups (“syncytial groups”)
– High N/C ratio
– Hyperchromatic nuclei
– Coarse chromatin
– Irregular nuclear contours
Atrophy vs. HSIL HSIL in Atrophy
Transitional cell metaplasia vs. HSIL Metaplasia vs. HSIL
Metaplasia HSIL
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SIL in Atrophy: Previously used Estrogen Stimulation Test
HSIL in atrophy
Atrophy: Abundant Inflammatory Exudate and Basophilic Granular Background and Histiocytes (atrophic vaginitis) Squamous cell carcinoma: Diathesis
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HSIL(CIN 3) and AIS
Review of the Pap Test: ASC‐H or HSIL
• Cells are hyperchromatic and difficult to see
• Cell fragments with linear, sharp edges, usually squamous
• Normal atrophy along with dark clusters
HSIL: Cytologic FeaturesCells occur singly, in sheets and in syncytial‐like aggregates.‐ Some aggregates appear as hyperchromatic crowded groups (HCGs).
‐ Small cells with less cytoplasmic maturity than LSIL.‐ Cytoplasm variable from “immature” metaplastic appearing to lacy to mature and densely keratinized.
‐ Marked increase in nuclear / cytoplasmic ratios.‐ Degree of nuclear enlargement more variable than in LSIL.‐ Altered chromatin (generally hyperchromatic).‐ Chromatin texture varies from fine to coarsely granular.‐ Prominent nuclear membrane irregularities with indentations and grooves.
‐ Nucleoli generally absent (possible with endocervical extension).
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TBS: Atrophy
• Negative for Intraepithelial Lesion or Malignancy
–Organisms
–Other non‐neoplastic findings (optional)
• Reactive cellular changes associated with
–inflammation (includes typical repair)
–radiation
–IUD
• Glandular cells post hysterectomy
• Atrophy
Atrophy
• These atrophic patterns can pose problems in interpretation of cervical smears due to a predominance of parabasal cells with a high nuclear to cytoplasmic ratio that are present in both singly and in syncytial‐like groups that may mimic HSIL.
• In atrophic vaginitis with inflammation, epithelial injury (repair/ulcer), infection, keratinization or degeneration may simulate SCC.
• Normal physiologic changes short of the full atrophic pattern, and atrophic vaginitis with nuclear enlargement may present cytologic features that may mimic other abnormal conditions such as the squamous atypia's‐ASC: ASC‐US or ASC‐H.
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1976 2016
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