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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 ratio
decreases
• Mitotic activity only in
parabasal 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
Squamous Metaplasia at TZ
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
Typical Location of SQ‐ Col Junction
Old and new TZ
Squamous Metaplasia
Age related changes
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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 .
Immature Squamous Metaplasia
ICN:35um2
ECN: 40um2
MCN:50um2
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Maturing 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
Endocervical/TZ component: 10 well‐preserved endocervical or squamous metaplastic cells singly or in clusters
Lower N/C ratio, with finely granular chromatin +/‐small nucleoli. With maturation lose muddy cytoplasm and nuclei begin to look more like IC.
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. 3
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“Maturation Index”
:
:
Parabasal cells
:
Atrophy: Parabasal Cells
Intermediate cells
:
Superficial cells
Atrophic pattern = absence of estrogen
MI = 0 S : 0-50 I : 50-100 PB
Squamous atrophy: Clinical setting associated with low estrogen state/decrease of hormonal support
Highly variable changes reflecting the differing levels of hormonal support
Atrophic Squamous Epithelium • 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
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”
Atrophy: Stripped nuclei (Should elicit search for classic intact HSIL).
Atrophy: Autolysis and degenerative changes. Uniform in size. Possible nucleoli. “
Blue blobs: Globular collections of basophilic amorphous material; degenerated parabasal cells or inspissated mucus.
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 unknown
R
ef: Am J Clin Pathol 2005;124:58‐61
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.
HSIL: Larger than ICN. Nuclear features of HSIL.
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 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. 5
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ASC in PM
Atypical Squamous Cells (ASC)
In atrophic smears
Bethesda: nuclear enlargement, hyperchromasia, irregularities in nuclear contour or chromatin or marked cellular pleomorphism (tadpole or spindle cells)
• 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
LSIL 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
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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 Atrophy: Hyperchromatic Crowded Groups
Parallel streaming arrangements of nuclei in cells that have indistinct relatively dense cyanophilic cytoplasm
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
• Neoplastic/Preneoplastic
– (ASC‐H)
– HSIL
– AIS
– Squamous cell carcinoma
• Adenocarcinomas
– Tubal metaplasia
– Micro‐glandular hyperplasia
– Clusters of inflammatory cells
HSIL: Cytologic Criteria
Single cells
Groups of cells
– Discrete parabasal‐
like cells
– High N/C ratio
– Irregular nuclear contours
– Marked hyperchromasia
– Coarse chromatin
– 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 HSIL: Cytologic Features
Review of the Pap Test: ASC‐H or HSIL
Cells 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).
• Cells are hyperchromatic and difficult to see
• Cell fragments with linear, sharp edges, usually squamous
• Normal atrophy along with dark clusters
TBS: Atrophy
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
• 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
Long hair
Longing for hair
Acid rock
Acid reflux
Moving to California
because it’s cool
Moving to Florida
because it’s warm
Trying to look like
Marlon Brando or Liz Taylor
Trying NOT to look like
Marlon Brando or Liz Taylor
Hoping for a BMW
Hoping for a BM
Going to a new, hip joint
Getting a new hip joint
Rolling Stones
Kidney stones
Disco
Costco
Passing the driver’s test
Passing the vision test
Whatever
Depends
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