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Pathology Journal Reading

Pathology Journal Reading. Presented by Intern 曾德朋. Objective. To identify the role of cytokeratins in distinguishing intraductal papilloma from papillary ductal carcinoma in situ. Introduction. Papillary breast tumors: Proliferated mammary epithelium projects into duct lumen

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Pathology Journal Reading

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  1. Pathology Journal Reading Presented by Intern 曾德朋

  2. Objective • To identify the role of cytokeratins in distinguishing intraductal papilloma from papillary ductal carcinoma in situ

  3. Introduction • Papillary breast tumors: • Proliferated mammary epithelium projects into duct lumen • Intraductal papilloma • Preinvasive papillary ductal carcinoma in situ (DCIS) • Sometimes difficult to distinguish: overlapping microscopic appearances

  4. The need to separate them… • Distinct biologic behavior • Papillary DCIS potentially progressing to invasive cancer • Surgical extirpation • Benign papillomas • Discharged from clinical follow up

  5. Cytokeratins (CK) • Fundamental markers of epithelial differentiation • Cell type & differentiation status • Previous studies: • CK5/CK6, 34BE12 and CK14 in distinguishing usual epithelial hyperplasia from atypical ductal hyperplasia (ADH) and DCIS • Presence of myoepithelial cells • Preserved in benign papillomas, scant in papillary DCIS • Muscle actin and 34BE12 (less specific)

  6. In this study… • Detail the expression of three CK antibody preparation • CK5/6 • CK14 • 34BE12 (recognizing CKs 1, 5, 10 and 14)

  7. Aim of this study… • determining their role (CKs) in differentiating the benign papilloma from malignant in situ papillary carcinoma • Scant literature that specifically addresses papillary lesions • previous work focusing on proliferative breast lesions as a generic group versus DCIS • Semiquantitative criteria of immunoscores to evaluate the CKs • Ascertain the findings by extrapolating to a separate group

  8. Materials and Methods • Patients and tumors • 50 excision biopsies of papillary breast lesions (25 intraductal papillomas and 25 papillary DCIS) • Department of Pathology, Singapore General Hospital, 2002~2003 • Variously reported by 14 general surgical pathologists - initially • Diagnostic review and assignment to papilloma and papillary DCIS by Pathologist P.H.T • Results were all in concordance with initial diagnosis

  9. Materials and Methods… • Cont… • Intraductal papillomas (25 cases) • Age: mean 44.1 y/o (22-78 y/o) • Epithelial hyperplasia of mild to florid degree • No atypical ductal hyperplasia • Papillary DCIS (25 cases) • Age: mean 57.4 y/o (35-78 y/o) • No invasive elements present

  10. Materials and Methods… • Cont… • 43 Hong Kong cases • As to confirm the result with a separate distinct cohort • Initial diagnosis: 10 general surgical pathologists • Histologically reviewed by pathologist G.M.T • Cases: age: mean 52.5 y/o • 1993 ~ 2001 • Excision biopsies 36 cases • Core biopsies 7 cases • Submitted for CK immunohistochemical staining at SGH, without prior discussion

  11. Materials and Methods… • Cont… • Immunohistochemistry • Human tonsil, squamous cell carcinoma and prostate: positive controls for CK5/6, CK14, and 34BE12, respectively • Normal ducts and ductules in the breast tissues: internal control

  12. Materials and Methods… • Cont… • Scoring of sections • Staining intensity: 0, no staining; 1+, weak; 2+, moderate; 3+, strong • Quantification of positivity (0%~100%) • Estimate of the percentage of stained tumor cells in the lesion • Immunoscores: multiplying the staining intensity with percentage positivity (0~300) • Negative or low (0~50); Moderate (51~100); High (101~200); Very high (201~300)

  13. Materials and Methods… • Cont… • Confocal microscopy • Statistical analysis • Two-tailed t test: differences in immunoreaction between the two sample groups • Positive predictive value: CK immunoscore of <50 • Papillary DCIS • Negaive predictive value: CK immunoscore of >50 • Papilloma • Reevaluate for cases with discrepancies

  14. Results: Cytokeratin expression in a normal breast ductule

  15. ImmunoreactionsIntraductal Papillomas and Papillary DCIS (SGH cases)

  16. ImmunoreactionsIntraductal Papillomas and Papillary DCIS (SGH cases) • CK5/CK6 • Papillomas • 72% : moderate to high immunoscores • Papillary DCIS • All: low immunoscores with 10 being completely negative • CK14 • Papillomas • 84% high to very high immunoscores • 16% moderate to low immunoscores • Papillary DCIS • 84% low immunoscores • 16% moderate immunoscores • 34BE12 • Papillomas • 56% high to very high immunoscores • 44% low to moderate • Papillary DCIS • 80% low • 20% moderate (1 case: high positivity)

  17. ImmunoreactionsIntraductal Papillomas and Papillary DCIS (SGH cases) • t test • Staining intensity, precetage positivity, immunoscores for each CK: • all three parameters showed significantly higher in papillomas than DCIS

  18. CK5/CK6 • CK5/CK6 expression in an intraductal papilloma (left panel) and • Papillary DCIS (right panel) • About half of the tumor cells in the papilloma were stained, whereas • tumor cells in DCIS were nonreactive

  19. CK14 • CK14 expression in an intraductal papilloma (left panel) and • Papillary DCIS (right panel) • More than half of the tumor cells in the papilloma were stained, • whereas tumor cells in DCIS were nonreactive

  20. 34BE12 • 34BE12 expression in an intraductal papilloma (left panel) and • Papillary DCIS (right panel) • Approximately half of the papilloma tumor cells were stained, • some DCIS tumor cells were also decorated

  21. Confocal microscopy of CKs

  22. Results… • Hong Kong cases • Immunoscores objectively determined by PHT (SGH) • CK5/CK6 corroborated • Papilloma 89.3% • Papillary DCIS 86.7% • CK14 • Papilloma 92.9% • Papillary DCIS 86.7% • 34BE12 • Papilloma 96.4% • Papillary DCIS 33.3%

  23. Discordant cases

  24. SGH and HK cases

  25. Statistic values…

  26. Discussion • Cytoskeleton • Microtubules, microfilaments and intermediate filaments (CKs belong to one of 5 classes of intermediate filaments) • CKs: cytoplasmic scaffold • Sustain mechanical and nonmechanical stresses • Participation in the response to stress, cell signaling and apoptosis • To date: 20 CKs (12: acidic type I; 8 neutral-basic type II)

  27. Discussion • Normal resting mammary gland • Epithelium lining • Inner luminal epithelial (LE) cells • CKs 7, 8, 18, 19 • Outer myoepithelial (ME) cells • CKs 5, 14, 17

  28. Discussion • Previous studies • Monoclonal antibodies specific against simple and/or basal type CKs • Benign and malignant intraepithelial proliferations of breast • Atypical proliferations • Invasive breast carcinomas No study compares the expression of basal-type CKs in papillary tumors

  29. Discussion • Our results • CK14 stained a significantly larger percentage of tumor cells in papilloma • Breast epithelium of proliferating mammary gland • 3 types of cells: immature precursor (CK5/CK6) intermediate (CK5/CK6, CK 8, 14, 18, 19), fully mature (CK14, 18, 19) • Intraductal papilloma • Larger proportion of fully mature cells

  30. Discussion • 34BE12 • Stained more DCIS tumor cells • Recognizes CK1, 10, 5, 14 • CK10 expressed in some LE cells in breast cancers (previous studies)

  31. Discussion • Results applied to a separate distinct cohort of HK cases, confirmation of • Benign papilloma diagnosis 89.3% (CK5/CK6) to 96.4% (34BE12) • Discordant cases: small or core biopsy • ADH case: necessity for microscopic reevaluation • Papillary DCIS (result at odds) • Core biopsy • Invasive component (detect LE as well) • Not as reliable or sensitive as the other 2 CKs • Apocrine nature

  32. In summary • The three CKs can serve as helpful adjunctive markers • Particularly combination of CK5/CK6 and CK14 • 34BE12: low detection rate • Especially in delineation of papillary DCIS • Use of CKs on small lesions, core biopsies, apocrine morphology, and associated invasive cancer need further evaluation

  33. Thank you for your attention

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