AnthonyOsei Safo

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• Anthony-Osei Safo
• AP Journal Club
• 21 June 2007

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Background

• Intraductal Papillary Mucinous Neoplasms (IPMNs)
  a type of pre-invasive cystic mucinous neoplasm
  of the pancreas
• Older pts., often in men, detectable masses in
  the head of the gland with cystic dilation of
  ducts and mucin hypersecretion
• Heterogeneous neoplasm with varying morphologic
  and IHC characteristics
• Varying proliferation of mucinous epithelium from
  simple to complex arborizing papillae
• 4 histologic variants based on morphologic and
  immunohistochemical characteristics

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(No Transcript)
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Introduction

• Fascin is an actin bundling protein (crosslinks
  actin filament)
• Fascin interacts with the wnt signaling pathway
  which culminates in a message being transduced to
  ß-catenin
• Involved in embryogenesis and carcinogenesis
• Morphology, proliferation, motility, and cell
  fate
• Fascin is required for the cellular migration and
  cell-matrix adhesion
• Forms actin-based cell-surface protrusions

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Study premise

• Fascin has been reported to be over expressed in
  other epithelial malignancies
• PanIN, a pre-invasive pancreatic neoplasm
• Fascin might be involved in the progression of
  IPMNs

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Objectives

• The aims of this study were
• 1. To analyze fascin expression in IPMN
  specimens
• 2. To clarify its relationship with
  clinicopathologic features (histologic grade
  phenotypic subtype)
• 3. To elucidate the association of fascin
  expression in the progression of IPMN.

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Materials Methods

• 116 samples of IPMN resected in a 19 year period
  (1986-2005)
• Lesions were sub-classified based on phenotype
  and MUC expression and graded based on the
  greatest degree of dysplasia (WHO classification
  of adenoma, borderline neoplasm, or carcinoma
  with/without invasion)
• 10 cases of conventional ductal carcinoma were
  analyzed for fascin expression by IHC
• 8 fresh-frozen samples of IPMNs were used for
  quantitative analysis of fascin mRNA expression
  after laser microdissection
• Molecular confirmation
• Transcriptional or post-transcriptional

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Clinicopathologic findings
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Materials Methods

• EVALUATION OF IHC STAINS
• Only in the area of highest dysplasia
• Positive cases had fine granular to diffuse
  cytoplasmic staining
• The proportion of fascin positivity was measured
  according to the age of fascin-positive tumor
  cells
• lt10 0 (considered negative)
• 10-30 1
• 30-60 2
• gt60 3
• All slides were independently evaluated by 2
  investigators without prior knowledge of the pt
  hx

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Negative for normal pancreas but positive for
endothelium and stromal fibroblasts.
Negative case for adenoma (Score 0)
Positive case of borderline neoplasm (Score 3)
Positive case of carcinoma (Score 3)
Positive for intraepithelial and invasive
components
Comparison b/n severe dysplasia and mild
dysplasia
Abrupt transition to normal ductal epithelium
Conventional pancreatic ductal adenocarcinoma
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Results
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Results

• Of the 116 IPMNs, 85 (73) demonstrated positive
  expression of fascin
• Fine granular to diffuse cytoplasmic staining
• The number of fascin-positive neoplasms were
  higher in borderline neoplasms (25/29) and
  carcinomas (37/42) than in adenomas (23/45)
• No difference was observed b/n borderline
  neoplasms and carcinomas
• Higher grade areas showed more diffuse and
  intense immunoreactivity
• Invasive components were positive in both tubular
  and colloid patterns
• I-type neoplasms (35/39) were more frequently
  positive for fascin than G-type neoplasms (36/59)
• 9/10 conventional ductal carcinomas were
  intensely positive
• Fascin mRNA over-expression was higher in
  moderately-severely dysplastic epithelium than in
  mildly-dysplastic epithelium
• Not statistically significant

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Results
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Correlation b/n grade and fascin score
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RT-PCR evaluation of fascin mRNA expression
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Conclusions

• Fascin was upregulated in the majority of IPMNs
  (73) and correlated with increased histologic
  grade
• Suggests fascin involvement in IPMN progression
• By IHC analysis, confirmed by molecular analysis
• Fascin upregulation occurs early in IPMN
  progression
• Expression was equally greater in borderline
  neoplasms (86) and carcinomas (88) than in
  adenomas (51)

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Conclusions

• Fascin over expression occurred more frequently
  in moderately to severely dysplastic epithelium
• 90 in I type IPMN versus 61 in G
• Unclear whether differences are due to histologic
  grade or subtype
• Oncocytic and pancreatobiliary type did not have
  high fascin expression
• Suggestive of different pathway of progression

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Criticisms

• Strengths
• Independent evaluation of slides by two
  investigators sans prior knowledge
• Sophistication of laser microdissection technique
• Appropriate statistical analysis
• Good presentation of results
• Title, authors, abstract
• Documentation, scientific conduct

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Criticisms

• Weaknesses
• Retrospective study
• No mention of how cases were selected
• Consecutive cases or hand-picked cases
• Slight objectivity in grading scale for age of
  fascin positive cells (under 10, 10-30, over 60)
• Sophistication of laser microdissection technique
• Too few frozen samples (n8)
• Study limitations are not addressed
• Fascin could become therapeutic target is
  unfounded

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Criticisms

• GENERAL STATEMENTS/IMPACT/RELEVANCE
• IHC analysis supported by molecular diagnostics
• Some conclusions were appropriately drawn and
  supported by results
• Unclear whether fascin upregulation is merely a
  marker of histologic grade or whether it plays a
  pathogenic role in progression of IPMNs
• O-type and PB-type IPMNs did not stain uniformly
  for fascin
• Unknown mechanism of fascin upregulation in IPMN
• More studies are needed to confirm the role of
  fascin IHC in IPMNs
• Relevance? (Was The Study Worth Doing?)
• I would not recommend fascin for IPMNs

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THE END!!!