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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

Pathology Journal Reading

Presented by Intern 曾德朋

objective
Objective
  • To identify the role of cytokeratins in distinguishing intraductal papilloma from papillary ductal carcinoma in situ
introduction
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
the need to separate them
The need to separate them…
  • Distinct biologic behavior
    • Papillary DCIS potentially progressing to invasive cancer
      • Surgical extirpation
    • Benign papillomas
      • Discharged from clinical follow up
cytokeratins ck
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)
in this study
In this study…
  • Detail the expression of three CK antibody preparation
    • CK5/6
    • CK14
    • 34BE12 (recognizing CKs 1, 5, 10 and 14)
aim of this study
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
materials and methods
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
materials and methods9
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
materials and methods10
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
materials and methods11
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
materials and methods12
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)
materials and methods13
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
immunoreactions intraductal papillomas and papillary dcis sgh cases16
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)
immunoreactions intraductal papillomas and papillary dcis sgh cases17
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
ck5 ck6
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
slide19
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
34be12
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
results
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%
discussion
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)
discussion27
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
discussion28
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

discussion29
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
discussion30
Discussion
  • 34BE12
    • Stained more DCIS tumor cells
      • Recognizes CK1, 10, 5, 14
      • CK10 expressed in some LE cells in breast cancers (previous studies)
discussion31
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
in summary
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