Maturation Index 3/29/2017. Disclosure of Relevant Financial Relationships. Gynecologic Cytology. Normal Maturation of Squamous Epithelium : :

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1 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 1

2 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 : 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 Squamous Metaplasia Old and new TZ Age related changes 2

3 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. ECN: 40um 2 ICN:35um 2 MCN:50um 2 14 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. 3

4 Maturation Index Atrophy: Parabasal Cells : : Parabasal cells : Intermediate cells : Superficial cells Atrophic pattern = absence of estrogen MI = 0 S : 0-50 I : PB 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 nonlactating 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 4

5 Atrophy: Degenerated parabasal cells Blue blobs Atrophy: Stripped nuclei (Should elicit search for classic intact HSIL). Degenerated or algophilic cells or eosinophilic parabasal cells with smudgy nuclei and pyknosis pseudo parakeratosis Atrophy: Autolysis and degenerative changes. Uniform in size. Possible nucleoli. Blue blobs: Globular collections of basophilic amorphous material; degenerated parabasal cells or inspissated mucus. HSIL: Larger than ICN. Nuclear features of HSIL. Atrophy: Generalized Nuclear Enlargement PM: Atypia vs. ASC 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 year olds Cause is unknown R ef: Am J Clin Pathol 2005;124:58 61 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. 5

6 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 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: and TBS 6

7 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. 7

8 Hyperchromatic Crowded Group: Grouping that impede the ability to see the individual cells in the middle HSIL: Cytologic Criteria Benign Neoplastic/Preneoplastic Endocervical cells (ASC H) Endometrial cells HSIL LUS AIS Atrophy Squamous cell carcinoma Tubal metaplasia Adenocarcinomas Micro glandular hyperplasia Clusters of inflammatory cells Single cells Discrete parabasallike 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 8

9 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 9

10 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 Features 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). 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 59 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. 10

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