. 2019 Jul 17;11(501):eaav4772.

doi: 10.1126/scitranslmed.aav4772.

A multimodality test to guide the management of patients with a pancreatic cyst

Simeon Springer^{1

2}, David L Masica^{2

3

4}, Marco Dal Molin^{2

5}, Christopher Douville^{1

2

3

4}, Christopher J Thoburn^{1

2}, Bahman Afsari^{2

6}, Lu Li^{1

2}, Joshua D Cohen^{1

2

3}, Elizabeth Thompson^{2

5}, Peter J Allen⁷, David S Klimstra⁸, Mark A Schattner⁹, C Max Schmidt¹⁰, Michele Yip-Schneider¹⁰, Rachel E Simpson¹⁰, Carlos Fernandez-Del Castillo¹¹, Mari Mino-Kenudson¹², William Brugge¹³, Randall E Brand¹⁴, Aatur D Singhi¹⁵, Aldo Scarpa^{16

17}, Rita Lawlor^{16

17}, Roberto Salvia¹⁸, Giuseppe Zamboni¹⁹, Seung-Mo Hong²⁰, Dae Wook Hwang²¹, Jin-Young Jang²², Wooil Kwon²², Niall Swan²³, Justin Geoghegan²⁴, Massimo Falconi²⁵, Stefano Crippa²⁵, Claudio Doglioni²⁶, Jorge Paulino²⁷, Richard D Schulick²⁸, Barish H Edil²⁸, Walter Park²⁹, Shinichi Yachida³⁰, Susumu Hijioka³¹, Jeanin van Hooft³², Jin He³³, Matthew J Weiss³³, Richard Burkhart³³, Martin Makary³³, Marcia I Canto³⁴, Michael G Goggins^{2

5

6

34}, Janine Ptak^{1

2}, Lisa Dobbyn^{1

2}, Joy Schaefer^{1

2}, Natalie Sillman^{1

2}, Maria Popoli^{1

2}, Alison P Klein^{1

2

6}, Cristian Tomasetti^{35

36}, Rachel Karchin^{3

4

6

35}, Nickolas Papadopoulos^{1

2}, Kenneth W Kinzler^{1

2}, Bert Vogelstein^{37

2}, Christopher L Wolfgang^{35

6

33}, Ralph H Hruban^{2

5

6

37}, Anne Marie Lennon^{37

2

6

33

34

38}

Affiliations

¹ Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
² Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA.
³ Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD 21287, USA.
⁴ Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
⁵ Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁶ Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁷ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁸ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁹ Department of Gastroenterology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
¹⁰ Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹¹ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹² Department of Histopathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹³ Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁴ Department of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA.
¹⁵ Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
¹⁶ ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy.
¹⁷ Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
¹⁸ General and Pancreatic Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
¹⁹ Department of Pathology, Ospedale Sacro Cuore-Don Calabria, Negrar 37024, Italy.
²⁰ Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
²¹ Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
²² Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea.
²³ Department of Histopathology, St. Vincent's University Hospital, Dublin D04 T6F4, Ireland.
²⁴ Department of Surgery, St. Vincent's University Hospital, Dublin D04 T6F4, Ireland.
²⁵ Division of Pancreatic Surgery, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
²⁶ Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
²⁷ Department of Surgery, Centro Hepatobiliopancreático e Transplantação, Hospital Curry Cabral, Lisbon 1050-099, Portugal.
²⁸ Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
²⁹ Department of Medicine, Stanford University Medical Center, Palo Alto, CA 94304, USA.
³⁰ Department of Hepatobiliary and Pancreatic Surgery, Pathology and Cancer Genomics, National Cancer Center Hospital and National Cancer Center Research Institute, Tokyo 104-0045, Japan.
³¹ Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
³² Department of Gastroenterology and Hepatology, Amsterdam Medical Center, Amsterdam 1017 ZX, Netherlands.
³³ Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁴ Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁵ Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA. bertvog@gmail.com amlennon@jhmi.edu cwolfga2@jhmi.edu rhruban@jhmi.edu ctomasetti@jhu.edu karchin@jhu.edu.
³⁶ Department of Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁷ Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA. bertvog@gmail.com amlennon@jhmi.edu cwolfga2@jhmi.edu rhruban@jhmi.edu ctomasetti@jhu.edu karchin@jhu.edu.
³⁸ Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, USA.

PMID: 31316009
PMCID: PMC7859881
DOI: 10.1126/scitranslmed.aav4772

A multimodality test to guide the management of patients with a pancreatic cyst

Simeon Springer et al. Sci Transl Med. 2019.

. 2019 Jul 17;11(501):eaav4772.

doi: 10.1126/scitranslmed.aav4772.

Authors

Affiliations

¹ Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
² Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA.
³ Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD 21287, USA.
⁴ Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
⁵ Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁶ Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁷ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁸ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁹ Department of Gastroenterology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
¹⁰ Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹¹ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹² Department of Histopathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹³ Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁴ Department of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA.
¹⁵ Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
¹⁶ ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy.
¹⁷ Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
¹⁸ General and Pancreatic Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
¹⁹ Department of Pathology, Ospedale Sacro Cuore-Don Calabria, Negrar 37024, Italy.
²⁰ Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
²¹ Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
²² Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea.
²³ Department of Histopathology, St. Vincent's University Hospital, Dublin D04 T6F4, Ireland.
²⁴ Department of Surgery, St. Vincent's University Hospital, Dublin D04 T6F4, Ireland.
²⁵ Division of Pancreatic Surgery, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
²⁶ Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
²⁷ Department of Surgery, Centro Hepatobiliopancreático e Transplantação, Hospital Curry Cabral, Lisbon 1050-099, Portugal.
²⁸ Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
²⁹ Department of Medicine, Stanford University Medical Center, Palo Alto, CA 94304, USA.
³⁰ Department of Hepatobiliary and Pancreatic Surgery, Pathology and Cancer Genomics, National Cancer Center Hospital and National Cancer Center Research Institute, Tokyo 104-0045, Japan.
³¹ Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
³² Department of Gastroenterology and Hepatology, Amsterdam Medical Center, Amsterdam 1017 ZX, Netherlands.
³³ Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁴ Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁵ Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA. bertvog@gmail.com amlennon@jhmi.edu cwolfga2@jhmi.edu rhruban@jhmi.edu ctomasetti@jhu.edu karchin@jhu.edu.
³⁶ Department of Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁷ Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA. bertvog@gmail.com amlennon@jhmi.edu cwolfga2@jhmi.edu rhruban@jhmi.edu ctomasetti@jhu.edu karchin@jhu.edu.
³⁸ Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, USA.

PMID: 31316009
PMCID: PMC7859881
DOI: 10.1126/scitranslmed.aav4772

Abstract

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.

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Figures

**Fig. 1.. Clinical features of all of the patients with pancreatic cysts.**
This heatmap shows the clinical features of the 862 patients with pancreatic cysts. Areas highlighted in black show the features present in the different types of cysts. For example, one can easily see that almost all the patients with MCNs were female, with cysts located in the body or tail of the pancreas. MPD, main pancreatic duct; PDAC, pancreatic ductal adenocarcinoma; MCN, mucinous cystic neoplasm; PanNET, pancreatic neuroendocrine tumor; SCN, serous cystic neoplasm; SPN, solid pseudopapillary neoplasm.

**Fig. 2.. Molecular features of all of the pancreatic cysts.**
This heatmap shows the molecular features of the 862 patients with pancreatic cysts. Areas highlighted in black show the features present in the different types of cysts. For example, one can see that *GNAS* mutations occur almost exclusively in patients with IPMN and PDAC and that they occur in cysts with all grades of dysplasia. In contrast, *SMAD4* mutations occur far more commonly in patients with PDAC or IPMNs with cancer or high-grade dysplasia than in patients with low- or intermediate-grade dysplasia.

**Fig. 3.. Clinical management of patients with pancreatic cysts.**
This figure shows how the type of pancreatic cyst determines the risk of the cyst developing cancer, which in turn dictates clinical management. Serous cystic neoplasms and pseudocysts have essentially no malignant potential and therefore require no monitoring. In contrast, cystic degeneration of a PDAC, PanNET, or solid pseudopapillary neoplasm are, or have a high risk for becoming, malignant, and therefore should undergo surgical resection. IPMNs and MCNs are mucin-producing cysts. A small number of these harbor high-grade dysplasia or cancer and should be surgically resected, while the remaining mucin-producing cysts simply need surveillance.

**Fig. 4.. Management of pancreatic cysts.**
These donut charts show the management recommendations based on CompCyst and standard of care compared with the gold standard, pathology. The center of the circle indicates the management recommendation based on the final surgical pathology classification. A fully solid circle—one where the inner and outer circles are fully the same color—would indicate 100% accuracy. The performance of CompCyst compared with surgical pathology for cysts in whom the correct management was discharge, monitoring, or surgery is shown in (A), (B), or (C), respectively. The performance of standard of care compared with surgical pathology is shown in (D), (E), or (F), respectively.

**Fig. 5.. Classification of the type of pancreatic cyst.**
These two heatmaps compare the CompCyst classification (A) and physician’s preoperative diagnosis based on clinical and imaging features (B) with surgical pathology for classifying the type of pancreatic cyst. The fraction of cysts classified to be of the indicated type is shown in the color bar.

See this image and copyright information in PMC

Comment in

Guiding pancreatic cyst management.
Bradley CA. Bradley CA. Nat Rev Gastroenterol Hepatol. 2019 Oct;16(10):582-583. doi: 10.1038/s41575-019-0198-7. Nat Rev Gastroenterol Hepatol. 2019. PMID: 31409907 No abstract available.

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A multimodality test to guide the management of patients with a pancreatic cyst

Affiliations

A multimodality test to guide the management of patients with a pancreatic cyst

Authors

Affiliations

Abstract

Figures

Comment in

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