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Plectin-1 is a Biomarker of Malignant Pancreatic Intraductal Papillary Mucinous Neoplasms

  • 2009 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery

Abstract

Introduction

Pancreatic intraductal papillary mucinous neoplasms (IPMN) are now identified with increasing frequency. The detection of carcinoma in IPMN is difficult and suffers from high false-positive and false-negative rates, often resulting in inappropriate treatment decisions. Improved detection of malignancy using novel biomarkers may therefore improve diagnostic accuracy. One such promising novel biomarker is Plectin-1 (Plec-1).

Methods

Using immunohistochemistry, Plec-1 expression was assayed in benign (low and moderate dysplasia, n = 6) as well as malignant IPMN (high-grade dysplasia and invasive carcinoma, n = 31) and lymph node metastases from carcinoma arising in IPMN (n = 12). Furthermore, cyst fluids from benign (n = 3) and malignant IPMN (n = 4) were evaluated for Plec-1 expression.

Results and discussion

Twenty-six of 31 malignant IPMN and all 12 lymph node metastases were Plec-1 positive. In contrast, only one of six benign IPMN expressed Plec-1. The specificity of Plec-1 in distinguishing malignant IPMN from benign IPMN was 83% and its sensitivity 84%. Furthermore, all (four out of four) cyst fluids from malignant IPMN, but none of the three benign IPMN, were Plec-1 positive. These data support Plec-1 as an excellent biomarker for the early detection of carcinoma arising in IPMN.

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Author information

Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114-2622, USA

    Dirk Bausch, Carlos Fernández-del Castillo & Andrew L. Warshaw

  2. Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114-2622, USA

    Mari Mino-Kenudson

  3. Department of Biomedical Engineering, University of Virginia, P.O. Box 800759, Health System, Charlottesville, VA, 22908, USA

    Kimberly A. Kelly

  4. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 15 Parkman St., WAC 460, Boston, MA, 02114-2622, USA

    Sarah P. Thayer

Authors
  1. Dirk Bausch
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  2. Mari Mino-Kenudson
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  3. Carlos Fernández-del Castillo
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  4. Andrew L. Warshaw
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Corresponding author

Correspondence to Sarah P. Thayer.

Additional information

Discussant

Dr. Edward Whang (BWU, Boston): Congratulations for a nice study, and congratulations on picking an excellent mentor with whom to work.

I have some tough questions, but I am sure you will be able to handle them.

First, some methodology questions: How did you pick the cases for inclusion in the study? Surely this is a very small subset of IPMNs available to study at MGH.

Also, I noticed the results you presented today are somewhat different from what you wrote in the abstract. In the abstract, you wrote that one of the colloid carcinomas expressed Plectin-1, whereas today, you said four of them expressed Plectin-1. Is there difficulty in interpretation of the immunohistochemistry in the examples that account for that difference?

Now for some philosophical questions: The sensitivity and specificity associated with using Plectin-1 expression status as a basis for distinguishing benign and malignant IPMNs are each less than 85%. Are those performance characteristics sufficient for clinical application?

Lastly, why is it important to differentiate benign from malignant IPMNs preoperatively? Is not the goal of surgery to prevent cancer from developing? Maybe what you really should seek is a biomarker that differentiates benign IPMNs that are destined to become cancer from benign IPMNs that are destined to remain benign for the remainder of the patient’s life.

Closing Discussant

Dr. Dirk Bausch: Invasive carcinoma arising in IPMN is a rare occurrence. Therefore, only a limited number of cases were available to us and included in the study. Benign IPMN and noninvasive malignant IPMN are much more common. For the purpose of the study, an equal number of main duct and branch duct IPMN were assayed. The relatively small number of benign cases compared to malignant cases assayed is a limitation of the study.

Colloid carcinoma cells contain a high amount of mucin, replacing most of the cytoplasm where Plectin-1 is normally identified. This made the evaluation of these samples exceedingly difficult. To accommodate for these difficulties, two independent observers evaluated all slides.

Sensitivity and specificity of Plectin-1 to detect malignant IPMN were about 85%. Currently employed screening methodology to detect malignancy in branch duct IPMNs, such as the international consensus criteria, have a sensitivity of only about 30%. Therefore, the clinical use of Plectin-1 as an additional screening modality may improve the sensitivity to detect malignancy in IPMN substantially.

The distinction between benign and malignant IPMN is important in the case of branch duct IPMNs, which have a relatively low risk of malignancy. Here, the risk associated with surgical therapy can outweigh the risk of malignancy, especially in the elderly population with small IPMNs.

However, it is important that a biomarker for IPMN identifies preinvasive carcinoma in situ, i.e., high-grade dysplasia lesions, whose prognosis is excellent after surgical resection. Plectin-1 identified about 80% of these cases.

Discussant

Dr. Joe Hines (UCLA): Let me ask the goal of this would be to take cyst aspirate to determine if it the cyst benign or malignant?

Closing Discussant

Dr. Dirk Bausch: The aim is to determine if a cyst is benign or malignant by assessing Plectin-1 expression in a cyst fluid aspirate. The goal is to exclude the operator dependency cytology suffers from and to substitute or augment it with an objective assay for Plectin-1.

Discussant

Dr. Joe Hines (UCLA): But my question is, is Plectin-1 shed into the fluid or does the analysis actually require cells? Because, as you said, the ability to access cytologic aspects for these types of lesion is highly unreliable.

Closing Discussant

Dr. Dirk Bausch: In this study, we used cyst fluids obtained from surgical specimens. Since all cyst fluids were centrifuged before being assayed, they should not contain cells. Therefore, Plectin-1 is most likely shed into the fluid itself. However, Plectin-1 content is very low in cyst fluid. Therefore, enrichment by immunoprecipitation was required prior to detection.

Discussant

Dr. Marc Basson (Michigan State University, East Lansing, MI): Do you think that you would you improve on your sensitivity and specificity if you combined the Plectin-1 reactivity with the other clinical criteria that are already in use. Have you gone back and looked at the numbers? I realize they are small.

Closing Discussant

Dr. Dirk Bausch: No such comparison was made in the current study. Our long-term goal is to improve overall sensitivity and specificity by using Plectin-1 together with clinical criteria.

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Bausch, D., Mino-Kenudson, M., Fernández-del Castillo, C. et al. Plectin-1 is a Biomarker of Malignant Pancreatic Intraductal Papillary Mucinous Neoplasms. J Gastrointest Surg 13, 1948–1954 (2009). https://doi.org/10.1007/s11605-009-1001-9

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