A potpourri of ASC-H and related interpretations-
                  Introduction                       Problem based learn...
A potpourri of ASC-H and related interpretations-
                                               Problem based learning


...
A potpourri of ASC-H and related interpretations-                                                     A potpourri of ASC-H...
A potpourri of ASC-H and related interpretations-                                                        A potpourri of AS...
A potpourri of ASC-H and related interpretations-                                                        A potpourri of AS...
A potpourri of ASC-H and related interpretations-                                                                     A po...
A potpourri of ASC-H and related interpretations-                                                                         ...
A potpourri of ASC-H and related interpretations-                                                                         ...
A potpourri of ASC-H and related interpretations-                                                                         ...
A potpourri of ASC-H and related interpretations-                                                     A potpourri of ASC-H...
11/13/2008




                                           Objectives
Study cases and application of
two-
two-color immunoc...
11/13/2008




Groups of atypical cells
       (without distinct cell borders)




                                       ...
11/13/2008




                   Case 2

          49 year old woman w/ a
          routine Pap test
                   ...
11/13/2008




Atrophic “ Single-cell” pattern
                                                                           ...
11/13/2008




                                     “School of fish” Repair – like pattern




                           ...
11/13/2008




   Follow up HPV –DNA test is Positive
    for high risk HPV types




       “Isolated cell pattern”
    ...
11/13/2008




         Follow up HPV –DNA test is Negative
          for high risk HPV types




               Atrophic...
11/13/2008




     Thank you

Thank you




                         8
11/13/2008




                                                    Multiple Slide Blinded Reviews as a
               ASC-...
11/13/2008




      Blinded Cytotechnologist
                                                Original Review Pap #2
     ...
11/13/2008




                                                           Blinded Cytotechnologist
           What do you ...
11/13/2008




        Original Review Pap #3
• Date: 4/21/05
• Diagnosis
    – Negative for intraepithelial lesion or
   ...
11/13/2008




      Original Review Pap #4
• Date: 6/1/06
• Diagnosis
  – Negative for intraepithelial lesion or
    mali...
11/13/2008




                                                              Blinded Cytotechnologist
           What do y...
11/13/2008




     ASC-H and HPV Testing
                                                  Atypical squamous cells, canno...
11/13/2008




                     Background                                                              GOALS
• 2001 A...
11/13/2008




                        Results                                                  Results
                  ...
11/13/2008




                          Results                           ASC-H w/ reflex hrHPV Testing
• ASC-H          ...
11/13/2008




       Summary of this study                                    Conclusions
• Significant difference in det...
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Potpouri Of Asc H Shidham Et Al (Wk#13 Asc Annual Meeting 2008)

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A potpourri of ASC-H and related interpretations- Problem based learning.
Shidham V, Chivukula M, Austin RM
Session Number: WK13

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Potpouri Of Asc H Shidham Et Al (Wk#13 Asc Annual Meeting 2008)

  1. 1. A potpourri of ASC-H and related interpretations- Introduction Problem based learning (Nov 11, 2008, 1.30 to 1.35) A potpourri of ASC-H and related interpretations- Problem based learning P bl b dl i Vinod B. Shidham, MD, FRCPath, FIAC Medical College of Wisconsin, Milwaukee, WI Mamatha Chivukula , MD Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA R. Marshall Austin, MD, PhD Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA A potpourri of ASC-H and related interpretations- Problem based learning Educational objectives Upon conclusion of this presentation, participants will be able to… 1. Describe cytomorphological spectrum of ASC-H. 2. Define LSIL-H with review of literature. 3. Differential diagnosis of hyperchromatic crowded groups. 4. Discuss application of ancillary tests. 1
  2. 2. A potpourri of ASC-H and related interpretations- Problem based learning A potpourri of ASC-H and related interpretations- Problem based learning P bl b dl i Shidham VB 1.35 to 2.15 (35 minutes + 5 minutes Q/A) Morphological Evaluation of Twilight Zone in Cervical Cytology. Chivukula M 2.15 t 1 55 Chi k l M. 2 15 to 1.55 (35 minutes + 5 minutes Q/A) i t i t Study cases and application of two-color immunochemistry Austin RM. 2.55 to 3.30 (30 minutes + 5 minutes Q/A) Quality Improvement, Ancillary HPV testing, and Medicolegal aspects 2
  3. 3. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning http://bethesda2001.cancer.gov/terminology.html Problem based learning (Nov 11, 2008, 1.35 to 2.15) Part I Morphological Evaluation of Twilight Zone in Cervical Cytology. Vinod B. Shidham, MD, FRCPath, FIAC Professor Executive editor & co-editor-in-chief, CytoJournal (www.cytojournal.com) Director- Cytopathology Fellowship Training Program & FNA Service Department of Pathology Medical College of Wisconsin 9200 W Wisconsin Av, Milwaukee, WI 53226, USA vshidham@mcw.edu A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning EPITHELIAL CELL ABNORMALITIES http://nih.techriver.net/ 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 1 High grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, CIS/CIN 2 and CIN 3 - with features suspicious for invasion (if invasion is suspected) Squamous cell carcinoma GLANDULAR CELL AGUS Atypical (NOS) - endocervical cells (NOS or specify in comments) - endometrial cells (NOS or specify in comments) - glandular cells (NOS or specify in comments) Atypical (favor neoplastic) - endocervical cells, favor neoplastic - glandular cells, favor neoplastic Endocervical adenocarcinoma in situ Adenocarcinoma - endocervical, endometrial, extrauterine, and not otherwise specified (NOS) OTHER MALIGNANT NEOPLASMS: (specify) A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 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 1 Atypical squamous cells High grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, CIS/CIN 2 and CIN 3 - with features suspicious for invasion (if invasion is suspected) Squamous cell carcinoma cannot exclude HSIL (ASC-H) (ASC H) GLANDULAR CELL AGUS Atypical (NOS) - endocervical cells (NOS or specify in comments) - endometrial cells (NOS or specify in comments) - glandular cells (NOS or specify in comments) Atypical (favor neoplastic) - endocervical cells, favor neoplastic - glandular cells, favor neoplastic Endocervical adenocarcinoma in situ Adenocarcinoma - endocervical, endometrial, extrauterine, and not otherwise specified (NOS) OTHER MALIGNANT NEOPLASMS: (specify) 1
  4. 4. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- ASC-H Problem based learning Normal vs ASC-H Problem based learning Source: Source: http://nih.techriver.net/patientImagesHighRes/6322.jpg?content-type=download http://nih.techriver.net/patientImagesHighRes/5568.jpg?content-type=download A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning ASC-H Problem based learning Source: http://nih.techriver.net/patientImagesHighRes/5866.jpg?content-type=download A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning ASC-H vs HSIL Problem based learning Source: http://nih.techriver.net/patientImagesHighRes/2064.jpg?content-type=download 2
  5. 5. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning The literature correlating different cytomorphological patterns with biopsy results?? A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 1. “Checker board” MGH – like pattern Cytomorphological Patterns of ASC-H. 1. MGH-like 2. Repair like - Dark nuclei 3A. Atrophy-like- with single cells - Smudgy chromatin - Nucleoli. Nucleoli 3B At h lik ith 3B. Atrophy-like- with HCG of parabasal cell groups f b l ll - Normoblast-like apoptosis 4. ASC-H: NOS confined to the area of nucleus 5. Cyanophilic small atypical parakeratotic cells 6A. HSIL- syncytial 6B. HSIL- Single cell Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 2. “School of fish” Repair – like pattern 3A. Atrophic “ Single-cell” pattern - Cohesive clusters -P i t l li Prominent nucleoli. - Ab d t blue cytoplasm Abundant bl t l - Low N/C ratio - Open chromatin - W/wout nucleoli Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 3
  6. 6. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 3B. Atrophic “ Parabasal cell groups” 5. Small Atypical parakeratotic cells - HCG of small parakeratotic cells - Sharp angulated cell margins (vs - HCG of parabasal cells p round peripheral borders of cells at - Small dark nuclei periphery of HSIL syncytium) - Variable, usually scant cytoplasm - Small koilocytes - Relatively high N/C ratio - Chromatin may be smudgy Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 6A. “Isolated cell pattern” 6B. “Syncytial cell” pattern -Groups of atypical cells - High N/C ratio (without distinct cell borders) - Hyperchromatic nuclei - Focal single-cell apoptosis single cell (with random distribution of apoptotic bodies) without nucleoli - Hyperchromatic nuclei - Coarse chromatin • (without nucleolar prominence) - Coarse to fine chromatin Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning Cytomorphological Patterns associated with different clinicopathological categories. Chivukula M, Shidham VB. ASC-H in Pap test- definitive categorization of cytomorphological spectrum. CytoJournal 2006, 3:14 doi:10.1186/1742-6413-3-14 Free full text is available at: http://www.cytojournal.com/content/3/1/14 PDF at: http://www.cytojournal.com/content/pdf/1742-6413-3-14.pdf Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 4
  7. 7. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 1. MGH-like pattern Shidham VB, Rao RN, Machhi J, Chavan A. Microglandular Hyperplasia has a cytomorphological spectrum overlappping with Atypical Squamous Cells- cannot exclude High-grade Squamous Intraepithelial Lesion (ASC-H). Groups of metaplastic cells arranged in checkerboard like pattern. The dark nuclei may show nucleoli (arrows). (A & b- Cervical smear [Papanicolaou stained SurePath™ Preparation], c- Cervical biopsy [Hematoxylin-eosin stained Diagnostic Cytopathology 2004 ;30:57-61. section]). Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 2. Repair-like pattern Shidham et al. Diagnostic Cytopathology 2004 ;30:57-61. Cohesive groups of cells with ill-defined school of fish pattern with relatively polarized cells with pointed ends (arrow head) show relatively low N/C ratio. The nuclei show nucleoli (arrows). (a & b- Cervical smear [Papanicolaou stained SurePath™ Preparation], c- Cervical biopsy [Hematoxylin-eosin stained section]). Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 3A. Atrophy-like pattern 3B. Atrophy-like pattern- Single cell pattern. HCG 0f Parabasal cell groups Cohesive hyperchromatic crowded groups of small parabasal cells with high N/C ratio. The nuclei are relatively Isolated cells with hyperchromatic atypical nuclei with smudgy chromatin). (a & b- Cervical smear [Papanicolaou small and show nucleoli (arrow). (a & b- Cervical smear [Papanicolaou stained SurePath™ Preparation], c- Cervical stained SurePath™ Preparation]). biopsy [Hematoxylin-eosin stained section]). Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 5
  8. 8. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning 4. ASC-H: NOS. 5. Cyanophilic Small Atypical parakeratototic cells Cohesive groups of hyperchromatic cyanophilic small atypical parakeratotic (SAPK) cells with ill-defined cell Cohesive groups of atypical cells with mostly ill-defined cell borders. The nuclei vary in size with coarse borders, which are straight with angulations better seen at periphery. N/C ratio is higher. Chromatin is smudgy. chromatin; however, the nuclear details in most are relatively smudgy (arrows). (a & b- Cervical smear Some cells may show koilocytic space around nuclei. (a & b- Cervical smear [Papanicolaou stained SurePath™ [Papanicolaou stained Sure-Path™ Preparation], c- Cervical biopsy [Hematoxylin-eosin stained section]). Preparation], c- Cervical biopsy [Hematoxylin-eosin stained section]). Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- 6A. HSIL pattern)- Syncytial pattern. Problem based learning 6B. HSIL pattern- Problem based learning Singly scattered (so called 'litigation') cells. Hyperchromatic crowded groups of cells without distinct cell borders. The hyperchromatic nuclei vary in size and Scattered, isolated, atypical cells show high N/C ratio. The nuclei have coarse chromatin without nucleoli (arrows). show coarsely granular chromatin (arrows). (a & b- Cervical smear [Papanicolaou stained SurePath™ Preparation], (a & b- Cervical smear [Papanicolaou stained SurePath™ Preparation], c- Cervical biopsy [Hematoxylin-eosin c- Cervical biopsy [Hematoxylin-eosin stained section]). stained section]). Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning Cytomorphological Patterns of ASC-H. Reactive In summary, 1. MGH-like our study identified 2. Repair like p y 3A. Atrophy like- with single cells g y p g p a cytomorphologic spectrum 3B. Atrophy like- with HCG of parabasal cell groups related with Indeterminate 4. ASC-H: NOS ASC-H interpretations, LSIL which demonstrated 5. Cyanophilic small atypical parakeratotic cells HSIL an association pattern 6A. HSIL- syncytial with the results of biopsy and HPV test. 6B. HSIL- Single-cell 6
  9. 9. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning Other Twilight Zone- Some unequivocal cases of LSIL may also be associated some atypical y yp cells suspicious for HSIL. How to evaluate them and how to report them? A dilema!!!!! A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning LSIL-H (with CIN2 & HPV in biopsy) Shidham VB, Kumar N, Narayan R, Brotzman GL. Should LSIL with ASC-H (LSIL-H) in cervical smears be an independent category? A study on SurePathTM Cervical smear with unequivocal LSIL in other fields. This field shows rare LSIL (a & c) with some groups of cells specimens with review of literature. consistent with ASC-H. The cells have a high N/C ratio with rounder curving cell borders (better seen in 'b'). At 20X CytoJournal 2007,4:7 (a), the ASC-H cell is difficult to focus because of three dimensional component in liquid based cytology. (a through Free full text is available at: http://www.cytojournal.com/content/4/1/7 c- Papanicolaou stained SurePathTM preps) PDF at: http://www.cytojournal.com/content/pdf/1742-6413-4-7.pdf Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning LSIL-H (with only HPV in biopsy) Biopsy results for LSIL, LSIL-H, ASC-H, and HSIL Cervical smear (a, b) showed unequivocal LSIL cells in other fields. This field shows rare LSIL (a & b) along with some groups of cells consistent with ASC-H. The biopsy (c) showed only human papilloma virus cytopathic effect. Small atypical parakeratotic (SAPK) cells with distinct and sharp angulated cell borders with tinge of cytoplasmic eosinophilia (arrowhead in b) (see also corresponding area in a) were interpreted as ASC-H component. (a & b- Papanicolaou stained SurePathTM preps, c- HE stained cervical biopsy Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 section). Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 7
  10. 10. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning LSIL-H as category overlap with LSIL and ASC-H, but was distinct from HSIL. Biopsy Keratinizing CIN 3 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations- Problem based learning Problem based learning Conclusions Suggested Management algorithm of Women with LSIL-H. LSIL-H as interpretation category is not a unique biologic entity. But it correlates with increased risk of high grade dysplasia on biopsy. Biopsy results pattern was intermediate between §Diagnostic excisional LSIL and ASC-H, but distinct from HSIL. procedure- Sampling of transformation zone and endocervical canal for histological evaluation with For optimal clinical management a separate group laser conization, cold-knife conization, loop of LSIL-H is justified. electrosurgical excision (LEEP), and loop electrosurgical conization. Application of molecular events such as p16 may Source: Chivukula M, Shidham V. be useful in the future. CytoJournal 2006, 3:14 A potpourri of ASC-H and related interpretations- Problem based learning End vshidham@mcw.edu Milwaukee Art Museum 8
  11. 11. 11/13/2008 Objectives Study cases and application of two- two-color immunochemistry  Present real time case studies to demonstrate the utility of cytomorphology in interpretation of y p gy p Mamatha Chivukula MD, FASCP, FCAP ASC- ASC-H pap tests Assistant Professor Associate Director of  Cytohisto correlation and follow-up follow- Immunohistochemistry lab HPV testing Magee- Magee-Women’s Hospital of UPMC Pittsburgh, PA Cytomorphology of ASC-H ASC- Case 1  MGH-like  Repair like  35 year old woman w/ a Atrophy-like- with single cells   Atrophy-like- with HCG of parabasal p y p routine Pap test cell groups  ASC-H: NOS  Cyanophilic small atypical parakeratotic cells  HSIL- syncytial  HSIL- Single cell 1
  12. 12. 11/13/2008 Groups of atypical cells (without distinct cell borders) -  Follow up HPV –DNA test is Positive for high risk HPV types Hyperchromatic nuclei - Coarse to fine chromatin “Syncytial cell” pattern Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 2
  13. 13. 11/13/2008 Case 2  49 year old woman w/ a routine Pap test - Abundantblue cytoplasm -Open chromatin,w/w out nucleoli  Follow up HPV –DNA test is Negative for high risk HPV types p16 KI -67 3
  14. 14. 11/13/2008 Atrophic “ Single-cell” pattern Case 3  30 year old woman w/ a routine Pap test Source: Chivukula M, Shidham V. CytoJournal 2006, 3: Cohesive clusters  Follow up HPV –DNA test is Negative for high risk HPV types -Prominent nucleoli P i t l li - Low N/C ratio 4
  15. 15. 11/13/2008 “School of fish” Repair – like pattern Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Case 4  35 year old woman w/ a routine Pap test 5
  16. 16. 11/13/2008  Follow up HPV –DNA test is Positive for high risk HPV types “Isolated cell pattern” Case 5  55 year old woman w/ a routine Pap test Source: Chivukula M, Shidham V. CytoJournal 2006, 3: - HCG of parabasal cells - Small dark nuclei - Variable, usually scant cytoplasm 6
  17. 17. 11/13/2008  Follow up HPV –DNA test is Negative for high risk HPV types Atrophic “ Parabasal cell groups” Application of two-color two- immunochemistry  P16 is over expressed and accumulates in nucleus and cytoplasm of dysplastic cervical cells  S di on ASC-US, ASC-H Studies ASC-US ASC-  Advanced kits for immunostaining cervical specimens to detect both p16 and ki-67 ki- simulatneously Source: Chivukula M, Shidham V. CytoJournal 2006, 3: State of the art….work in progress  In a normal cell w/ intact cell cycle, Simultaneous expression of anti-proliferative anti- marker (p16), proliferative marker (ki-67) (ki- within the same cell, mutually excludes each other  Reversely, presence of both p16, ki-67 in ki- the same cell, indicates disrupted cell cycle 7
  18. 18. 11/13/2008 Thank you Thank you 8
  19. 19. 11/13/2008 Multiple Slide Blinded Reviews as a ASC-H: Quality Improvement Tool Quality Improvement, Ancillary HPV • Identify Pap tests screened as negative or testing, and Medicolegal aspects equivocally abnormal preceding subsequent diagnoses of CIN2/3, AIS, or cervical cancer. • Insert Pap tests of interest into 10-20 slide 1) Highlight blinded review quality cytology challenge sets sets. improvement technique employed at MWH to enhance ASC-H detection • Ask staff cytotechnologists to rescreen and 2) medicolegal ramifications of disputed interpret all cases on anonymous answer retrospective ASC-H interpretations. sheets. 3) Unpublished data on the usefulness of • Review rescreening findings with staff along with HPV testing in the largest series reported to histologic and cytologic follow-up. date from MWH Original Review Pap#1 Paps #1 and 2 • Date: 4/7/03 Two Negative Paps Preceding • Diagnosis CIN2 Biopsy Result – Negative for intraepithelial lesion or malignancy. malignancy – Inflammatory changes. What do you think? • Negative • Cancer • Suspicious for cancer • HSIL • AGC (Atypical glandular cells) • ASC-H • LSIL • ASCUS 1
  20. 20. 11/13/2008 Blinded Cytotechnologist Original Review Pap #2 Review Results • Negative: 9 • Date: 3/26/04 • LSIL: 1 • Diagnosis • ASC-US: 4 – Negative for intraepithelial lesion or malignancy. malignancy Retro-review Diagnosis knowing outcome: – Inflammatory changes. Atypical Squamous Cells cannot exclude HSIL (ASC-H) 2
  21. 21. 11/13/2008 Blinded Cytotechnologist What do you think? Review Results • Negative • Negative: 9 • Cancer • ASC-US: 4 • Suspicious for cancer • HSIL • AGC (Atypical glandular cells) Retro-review Diagnosis knowing outcome: • ASC-H Atypical Squamous Cells cannot exclude • LSIL HSIL (ASC-H) • ASCUS Subsequent Surgical Pathology Result Paps #3 and 4 • Date: 1/4/07 • Diagnosis: Two Negative Paps Preceding – Cervical intraepithelial neoplasia 2 (CIN 2) CIN2 Biopsy Result 3
  22. 22. 11/13/2008 Original Review Pap #3 • Date: 4/21/05 • Diagnosis – Negative for intraepithelial lesion or malignancy malignancy. – Repair. Blinded Cytotechnologist What do you think? Review Results • Negative • Negative: 8 • Cancer • Atypical glandular cells: 1 • Suspicious for cancer • ASC-H: 2 • HSIL • ASC-US: 2 • AGC (Atypical glandular cells) • ASC-H Retro-review Diagnosis knowing outcome: • LSIL Atypical Squamous Cells cannot exclude HSIL (ASC-H) • ASCUS 4
  23. 23. 11/13/2008 Original Review Pap #4 • Date: 6/1/06 • Diagnosis – Negative for intraepithelial lesion or malignancy. malignancy – Adequate with cocci partially obscuring 50- 75% of epithelial cells. 5
  24. 24. 11/13/2008 Blinded Cytotechnologist What do you think? Review Results • Negative • Negative: 2 • Cancer • HSIL: 4 • Suspicious for cancer • ASC-H: 5 • HSIL • ASC-US: 2 • AGC (Atypical glandular cells) • ASC-H Retro-review Diagnosis knowing outcome: • LSIL • ASCUS High-grade squamous intraepithelial lesion (HSIL) Subsequent Surgical Multiple Slide Blinded Review Pathology Result (MSBR) Conclusions • Difficult to diagnose ASC-H cases may be • Date: 1/4/07 best recognized only with the hindsight bias • Diagnosis: of later known histologic outcome. – Cervical intraepithelial neoplasia 2 (CIN 2) • Standard of practice- what a reasonable peer who do under similar circumstances circumstances- is different from hindsight bias-influenced retrospective review. • ASC Pap Litigation Guidelines state that a violation of the standard of practice can ONLY be confirmed with MSBR. 6
  25. 25. 11/13/2008 ASC-H and HPV Testing Atypical squamous cells, cannot exclude HSIL MWH Experience p (ASC-H) subcategory was introduced in the 2001 Bethesda System. -“Atypical (immature) Metaplasia” : small cells with high N/C ratios. -“Crowded Sheet Pattern” Background Background • Mimics: • Atrophy • Incidence of ASC-H: 0.22% - 1.09% • Reactive/reparative change • Naked nuclei • Reported rate of CIN 2/3 on histologic follow- •P k t i Parakeratosis up: 12 2% - 68 2% 12.2% 68.2% • Immature metaplastic cells • Reported rates of high-risk HPV + in ASC-H: 33.3% - 85.6% Background Background on ALTS • All patients had previous ASC-US or LSIL • 2006 Consensus Follow-up Guidelines pap on conventional smears based on from the American Society for Colposcopy 1991 Bethesda terminology. and Cervical Pathology (ASCCP) • Participants had liquid-based Pap and – ASC H ASC-H go to colposcopy HPV testing. – Based on data from the ASCUS / LSIL Triage Study (ALTS) • Diagnosis was made by 4 pathologists • 110 ASC-H cases; 84% + hrHPV • Younger than average patient population. - Median age 24 years old. 7
  26. 26. 11/13/2008 Background GOALS • 2001 ASCCP guidelines for ASC-US • Evaluate: recommend “reflex” HPV DNA testing when – ASC-H paps liquid-based cytology is used. – High-risk HPV (hrHPV) DNA test results – ~ 85% of ASC-US paps get reflex HPV testing. ASC US – Histologic follow up follow-up • Some studies suggest that HPV testing may – Presence or absence of endocervical/ help triage ASC-H patients and reduce the transformation zone (EC / TZ) number of colposcopies. • Affect on detection of CIN • Affect on hrHPV detection Materials and Methods Materials and Methods • July 1, 2005 – December 31, 2007 • Histologic follow-up • ThinPrep Imaging System (TIS) was used – Endocervical curettage – ASC-H called when small, rounded, squamous cells with dense – Cervical biopsy limited cytoplasm, enlarged and euchromatic or hyperchromatic – Cervical conization (loop or cold knife cone) nuclei and some degree of nuclear membrane irregularities were identified • Two surgical pathologists confirmed CIN – EC/TZ status based on Bethesda 2001. diagnoses. • High-risk HPV DNA testing via Hybrid – CIN1 Capture II (HC2) – CIN 2 or higher (CIN2/3) – Ordered by clinicians as reflex for ASC pap, women > 30 y.o., or • Stratified according to age and EC/TZ HPV regardless. status. Results • ASC-H interpretations – 1646 (1619 ThinPrep, 27 conventional) – 0.59% of all paps • 0.60% in TP, 0.38% in conv. – 1187 (of TP) 73.3% had hrHPV testing done • Presence or absence of EC/TZ made no difference with regard to hrHPV DNA detection or detection of CIN 2/3 8
  27. 27. 11/13/2008 Results Results 926 with ASC-H & hrHPV testing 421 No histology 505 w/ at least 1 cervical bx* bx 257 (50.9%) hrHPV + 248 (49.1%) hrHPV - The difference in hrHPV + was significant between women <40 y.o. and women >40 y.o. *101 women had two or more biopsies Results Results 257 (50.9%) HPV + 248 (49.1%) HPV - 160 (62.3%) CIN 35 (14.1%) CIN • Cumulative CIN detection rate was 38.6% (195/505) • CIN 2/3 in 87 (17.2%) of 505 ASC-H & hrHPV tested patients Results Results (Table 4) • Statistical difference (P < .001) between hrHPV+ w/ CIN 2/3 and hrHPV – w/ CIN 2/3. • Women 30 -39 y.o. w/ + hrHPV had the greatest • 35.8% of HPV+ women < 40 y.o. had CIN 2/3; risk. • 20.8% of HPV+ women > 40 y.o. had CIN 2/3 • 4 women had AIS; all were hrHPV + 9
  28. 28. 11/13/2008 Results ASC-H w/ reflex hrHPV Testing • ASC-H PPV of CIN2/3 = 17.2% < 40 y.o. <40 y.o. Sensitivity 96.1% 100% • ASC-H and + hrHPV PPV of CIN2/3 = 32.7% Specificity 54% 68.4% PPV 35 8% 35.8% 20.8% 20 8% • ASC-H and – hrHPV NPV of no CIN2/3 = NPV 98.1% 100% 98.8% Comment Comment • Some abstracts report increased ASC-H reporting with the use of the ThinPrep Imaging System (TIS) – Decreased detection of hr HPV – Decreased detection of CIN 2/3 CAP interlaboratory comparison program Comment Why so much variability in hrHPV detection rates? • Differences in cytologic interpretation threshold for ASC-H ALTS • Undercalling of HSIL • Overcalling of ASC-H as HSIL ASC H • Overcalling metaplastic cells as ASC-H • Different patient populations – Rate of hrHPV + varies from 2.9% (current study) - 32.7% (ALTS) – ALTS median age 24 y.o.; this study median age 30 y.o. 10
  29. 29. 11/13/2008 Summary of this study Conclusions • Significant difference in detection of CIN in + hrHPV than negative. • Using both Pap test and high-risk HPV DNA testing allows for effective risk stratification of patients: • The negative predictive value of – hrHPV in ASC-H i ASC H was 100% i women > 40 y.o. in – HPV + to colposcopy – HPV – to follow-up with regular Pap and hrHPV testing. • Highest CIN 2/3 detection rate was in women 30-39 y.o. with ASC-H and + hrHPV 11

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