Sushanth Reddy, M.D.

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The Rants and Tirades of a Maniacal Senior
Surgery Resident

• Sushanth Reddy, M.D.
• General Surgery Resident
• University of Kentucky

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Last year.
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Pancreatic Cystic Lesions
All Right, No Basic Science.
Pseudocysts 120,000
Serous Cystadenomas 13,500,000
Mucinous Cystic Neoplasms 150,000
IPMN 1150,000
Reddy S, Wolfgang CL. Surg Clin North Am, 2007
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Whats an IPMN?!!
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Intraductal Papillary Mucinous Neoplasms

• 1980 Japanese report 4 patients with pancreatic
  cancer
• All had dilated pancreatic duct, mucinous
  features, patulous ampulla
• All 4 survived at least 3 years
• Over next decade mucinous ductal ectasia,
  mucinous pancreatic tumor, mucin producing
  carcinoma of the pancreas, intraductal papillary
  hyperplasia, intraductal papillary neoplasm, and
  intraductal mucin producing tumor

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Intraductal Papillary Mucinous Neoplasms

• 1997 MGH suggested the term Intraductal
  Papillary Mucinous Neoplasms (IPMN)

IPMN
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PubMed Search Term intraductal papillary
mucinous neoplasms pancreas accessed 1/6/10
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Why Are IPMN Important?

• IPMN have malignant potential
• There are ABSITE questions about them
• They can degenerate into cancer
• WHO Classification
• Low Grade Dysplasia
• Moderate Grade Dysplasia
• High Grade Dysplasia
• Invasive Cancer
• All IPMN have dysplasia!!

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IPMN with Cancer

• Pancreatic adenocarcinoma is associated with poor
  survival
• Margin negative, node negative 5 year survival
  15-20
• Lance Armstrong Foundation We dont fund
  non-curable diseases

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Poultsides GA, Reddy S, et al. Ann Surg in press
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IPMN - Associated vs. Standard Pancreatic
Adenocarcinoma Pathologic Characteristics
IPMN-associated Invasive Adenocarcinoma n 132 Standard Pancreatic Adenocarcinoma n 1128 P
Invasive Carcinoma Size (median, cm) Invasive Carcinoma Size (median, cm) 2.6 3.0 0.15
T stage T1 27 4 lt 0.001
T stage T2 21 10 lt 0.001
T stage T3 48 83 lt 0.001
T stage T4 4 3 lt 0.001
Nodal Metastasis Nodal Metastasis 51 78 lt 0.001
Poor Differentiation Poor Differentiation 26 44 lt 0.001
Vascular Invasion Vascular Invasion 33 54 lt 0.001
Perineural Invasion Perineural Invasion 63 92 lt 0.001
Margin Involvement Margin Involvement 14 28 lt 0.001
Poultsides GA, Reddy S, et al. Ann Surg in press
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IPMN - Associated Invasive AdenocarcinomaHistolog
ic Subtypes
Pancreatobiliary type IPMN (Aggressive
Pathway)
Tubular Adeno-carcinoma
Intestinal type IPMN (Indolent Pathway)
Colloid Carcinoma
Adsay NV, et al. Am J Surg Pathol. 2004
Jul28(7)839-48
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IPMN - Associated Invasive AdenocarcinomaPatholog
ic Characteristics
Tubular n 92 Colloid n 35 Anaplastic n 5 P
Overall Size (median, cm) Overall Size (median, cm) 3.5 5 6.5 0.002
Invasive Component Size (median, cm) Invasive Component Size (median, cm) 2.5 2.5 5.5 0.428
T stage T1 23 40 20 0.197
T stage T2 20 23 20 0.197
T stage T3 53 34 60 0.197
T stage T4 4 3 - 0.197
Nodal Metastasis Nodal Metastasis 59 29 80 0.003
Poor Differentiation Poor Differentiation 28 11 100 0.002
Vascular Invasion Vascular Invasion 42 7 33 0.001
Perineural Invasion Perineural Invasion 69 48 50 0.071
Margin Involvement Margin Involvement 18 0 40 0.006
comparison of tubular vs. colloid carcinoma comparison of tubular vs. colloid carcinoma comparison of tubular vs. colloid carcinoma comparison of tubular vs. colloid carcinoma comparison of tubular vs. colloid carcinoma comparison of tubular vs. colloid carcinoma
Poultsides GA, Reddy S, et al. Ann Surg in press
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Poultsides GA, Reddy S, et al. Ann Surg in press
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IPMN Related Cancers

• Given the favorable prognosis associated with
  IPMN associated cancers, an aggressive approach
  toward resection should be advocated
• Is the favorable outcome due to an inherent
  biologic difference or from an earlier
  presentation from the same cancer?

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Selection for Resection

• Which patients with IPMN should be resected?
• Lesions with cancer
• How do we know??
• High Grade Dysplasia?
• Theoretically the last step until invasive cancer
• Moderate or Low Grade Dysplasia?

YES
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Progression to Cancer
Sohn TA, Yeo CJ, et al. Ann Surg 2004
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Progression to Cancer

• Large autopsy series show that PanINs are present
  in 18-29 of non-cancerous pancreata

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Selection for Resection

• Should HGD, MGD, or LGD be removed?
• Pancreatic resection is associated with high
  morbidity and mortality
• Most authors report presence of invasive cancer
  or malignancy in IPMN
• Malignancy invasive cancer HGD

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Selection for Resection

• Consensus guidelines for management of IPMN
• 11th Congress of International Association of
  Pancreatology (IAP) Sendai Criteria
• Resection indicated for
• all main duct and combined type IPMN
• branch duct IPMN if
• size gt 30 mm
• mural nodule
• Symptomatic

Tanaka M et al. Pancreatology 2006
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Selection for Resection

• International consensus guidelines based on
  retrospective review of 8 studies of resected
  IPMN 475 patients (median 52 patients/study)
• Controversy over how to manage branch duct
  lesions
• Is it safe to follow small (lt 3 cm), asymptomatic
  branch duct IPMN without a solid component?

Cancer Malignancy
MD-IPMN 23-57 63-92
BD-IPMN 0-31 6-46
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Branch Duct Lesions

• Recommendations for branch duct IPMN based on 2
  studies
• 16 patients with BD-IPMN None had invasive
  cancer in lesions lt 3 cm
• 32 patients with BD-IPMN 12/17 BD-IPMN gt 3 cm
  had invasive cancer
• The paper did not clarify if these lesions were
  asssociated with solid components or symptoms
• A multivariate analysis was performed and size
  was predictive (OR 31.15, p 0.009)

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Branch Duct Lesions

• Appear to behave differently than MD- or combined
  type IPMN
• Lower incidence of malignancy and invasive cancer
• Pancreatic resection associated with significant
  morbidity
• Management guided by two studies with 33 patients
  between them!!

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Malignancy in IPMN of the Pancreas

• Main duct diffuse or segmental dilatation of the
  main pancreatic duct (MPD) gt 5 mm without
  associated cystic lesion
• Schmidt CM et al. Ann Surg 2007
• Kawamoto S, Fishman EK et al. AJR 2006

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Malignancy in IPMN of the Pancreas

• Branch duct dominant cystic lesion without MPD
  dilatation
• Schmidt CM et al. Ann Surg 2007
• Kawamoto S, Fishman EK et al. AJR 2006

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Malignancy in IPMN of the Pancreas

• Combined cystic lesion with MPD dilatation gt 5
  mm
• Schmidt CM et al. Ann Surg 2007
• Kawamoto S, Fishman EK et al. AJR 2006

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Malignancy in IPMN of the Pancreas
Main duct n 36 (12) Combined type n 123 (42) Branch duct n 137 (46)
Age (median, yrs) 72 70 68
Male gender 44 50 55
Symptomatic 75 74 47
Type of Resection
Whipple 28 71 73
Distal 33 13 22
Total 39 15 1
Central 0 1 4
Size (median, cm) 2 3.3 3
High Grade Dysplasia 22 21 20
Invasive carcinoma 58 56 27
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Malignancy in IPMN of the Pancreas
Branch duct IPMN (n 137) Branch duct IPMN (n 137) Branch duct IPMN (n 137) Branch duct IPMN (n 137)
Low/moderate grade dysplasia (n 73) High grade dyplasia (n 27) Invasive carcinoma (n 37) p-value
Age (median, yrs) 66 66 68 0.53
Male Gender 49 56 65 0.30
Location in head/uncinate 71 85 65 0.19
Size (median, cm) 2.6 3.1 5.2 lt 0.001
Size gt 3 cm 35 56 87 lt 0.001
Solid component 26 32 100 lt 0.001
Any symptom 42 52 76 0.003
Weight loss 14 19 27 0.24
Abdominal pain 38 44 54 0.32
Jaundice 1 7 24 lt 0.001
Nausea/vomiting 6 15 3 0.17
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Malignancy in IPMN of the Pancreas
Multivariate Analysis Preoperative Predictors of
Invasive Cancer in Branch Duct IPMN
OR 95 Confidence Interval 95 Confidence Interval p-value
Solid component 124.3 8.7 Infinity lt 0.001
Symptoms 5.7 1.6 20.9 0.008
Size gt 3 cm 3.7 0.86 15.9 0.077
Size (continuous) 1.4 0.99 1.92 0.051
Male gender 1.1 0.3 4.2 0.85
Location in head/uncinate 0.6 0.15 2.14 0.39
Age (continuous) 1.05 0.98 1.12 0.10
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Malignancy in IPMN of the Pancreas
Solid Component and Branch Duct Lesions
Solid Component (n 62) No Solid Component (n 68) p-value
Age (median, yrs) 66 70 0.37
Male Gender 62.9 50.0 0.16
Location (head/uncinate) 70.6 69.4 1.0
Size (median, cm) 4.0 2.2 lt 0.0001
Symptomatic 61.3 45.6 0.08
Abd Pain 48.4 41.8 0.48
Jaundice 14.5 3.0 0.03
Weight Loss 22.6 14.9 0.37
Nausea/Vomiting 8.1 6.0 0.74
Invasive Cancer 58.0 0 lt 0.0001
High Grade Dysplasia 12.9 25.0 0.53
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Malignancy in IPMN of the Pancreas

• Branch-duct IPMN without solid
  component (n 68)
• All without invasive carcinoma
• Incidence of high grade dysplasia (25) did not
  correlate with
• size gt 3 cm (p 0.15)
• presence of symptoms (p 0.59)

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Malignancy in IPMN of the Pancreas
Author Year Main duct and Combined type Main duct and Combined type Main duct and Combined type Branch duct Branch duct Branch duct
Author Year n Malignancy Invasive Carcinoma n Malignancy Invasive Carcinoma
Choi 2003 34 85 - 12 25 -
Kitagawa 2003 37 65 54 26 35 31
Sugiyama 2003 30 70 57 32 40 9
Sohn 2004 69 - 45 40 - 30
Salvia 2004 140 60 42 - - -
Rodriguez 2007 - - - 145 22 11
Schmidt 2007 53 57 28 103 19 14
Schnelldorfer 2008 124 52 - 84 18 -
Reddy 2009 159 78 57 137 47 27
Including high grade dysplasia (in situ) and invasive carcinoma Including high grade dysplasia (in situ) and invasive carcinoma Including high grade dysplasia (in situ) and invasive carcinoma Including high grade dysplasia (in situ) and invasive carcinoma Including high grade dysplasia (in situ) and invasive carcinoma Including high grade dysplasia (in situ) and invasive carcinoma Including high grade dysplasia (in situ) and invasive carcinoma Including high grade dysplasia (in situ) and invasive carcinoma
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Malignancy in IPMN of the Pancreas

• Prospective, single-arm, observational study
• 82 patients with branch duct IPMN
• no mural nodules
• asymptomatic
• median lesion size 2.0 cm (range, 1.1 4.5 cm)
• 12 of patients with lesions gt 3 cm
• Median follow-up 61 months
• 13 patients had radiologic progression
• 9 tumors enlarged
• 4 developed mural nodules
• 7 of 13 patients underwent surgical resection
• None had invasive cancer and one had high grade
  dysplasia
• Tanno S et al. Gut 2008

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Summary

• Invasive cancers associated with IPMN have
  favorable survival compared to standard
  pancreatic adenocarcinomas
• Survival benefit may be due to earlier
  presentation of the same lesion or a biologically
  different entity
• Main duct and combined type IPMN are more likely
  to have an invasive cancer than branch duct IPMN
• Presence of a solid component strongly correlated
  with invasive cancer in branch duct lesions
• Branch duct IPMN without a solid component did
  not have invasive cancer but did have high grade
  dysplasia

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Summary

• In accordance with the IAP guidelines, main duct
  and combined type IPMN or branch duct IPMN with
  solid component have a strong association with
  malignancy and warrant surgical resection.
• Branch duct IPMN without a solid component did
  not harbor invasive carcinoma regardless of size.
  Similarly, size did not predict the presence of
  high grade dysplasia.
• Size gt 3cm alone should be re-evaluated as an
  absolute indication for resection of branch duct
  IPMN without a solid component.
• Presence of a solid component is the strongest
  predictor of invasive cancer in branch-duct IPMN.