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Pathology Journal Reading

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Presentation on theme: "Pathology Journal Reading"— Presentation transcript:

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
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 Immunoreactions Intraductal Papillomas and Papillary DCIS (SGH cases)

16 Immunoreactions Intraductal 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 84% high to very high immunoscores 16% moderate to low immunoscores 84% low immunoscores 16% moderate immunoscores 34BE12 56% high to very high immunoscores 44% low to moderate 80% low 20% moderate (1 case: high positivity)

17 Immunoreactions Intraductal 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% 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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