A novel approach for selecting combination clinical markers of pathology applied to a large retrospective cohort of surgically resected pancreatic cysts

Masica, David L.; Molin, Marco Dal; Wolfgang, Christopher L.; Tomita, Tyler M.; Ostovaneh, Mohammad Reza; Blackford, Amanda L.; Moran, Robert A.; Law, Joanna K.; Barkley, Thomas; Goggins, Michael; Canto, Marcia Irene; Pittman, Meredith E.; Eshleman, James R.; Ali, Syed Z.; Fishman, Elliot K.; Kamel, Ihab R.; Raman, Siva P.; Zaheer, Atif; Ahuja, Nita; Makary, Martin A.; Weiss, Matthew J.; Hirose, Kenzo; Cameron, John L.; Rezaee, Neda; He, Jin; Ahn, Young Joon; Wu, Wen-Chuan; Wang, Yuxuan; Springer, Simeon; Diaz, Luis L.; Papadopoulos, Nickolas; Hruban, Ralph H.; Kinzler, Kenneth W.; Vogelstein, Bert; Karchin, Rachel; Lennon, Anne Marie

doi:10.1093/jamia/ocw069

Cited by 33 publications

(25 citation statements)

References 22 publications

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“…In this area, the mathematic modeling seems to be a worthwhile perspective, similar to in other tumor types [57,59,60,79,80]; here too, however, the complexity of the tumor architecture could be a major limitation. The extreme heterogeneity of prostate cancer at the metastatic disease stage also warrants further studies.…”

Section: Genetic/molecular Heterogeneitymentioning

confidence: 99%

The Heterogeneity of Prostate Cancer: A Practical Approach

Tolkach¹,

Kristiansen²

2018

Pathobiology

102

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Prostate cancer is a paradigm tumor model for heterogeneity in almost every sense. Its clinical, spatial, and morphological heterogeneity divided by the high-level molecular genetic diversity outline the complexity of this disease in the clinical and research settings. In this review, we summarize the main aspects of prostate cancer heterogeneity at different levels, with special attention given to the spatial heterogeneity within the prostate, and to the standard morphological heterogeneity, with respect to tumor grading and modern classifications. We also cover the complex issue of molecular genetic heterogeneity, discussing it in the context of the current evidence of the genetic characterization of prostate carcinoma; the interpatient, intertumoral (multifocal disease), and intratumoral heterogeneity; tumor clonality; and metastatic disease. Clinical and research implications are summarized and serve to address the most pertinent problems stemming from the extreme heterogeneity of prostate cancer.

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Section: Genetic/molecular Heterogeneitymentioning

confidence: 99%

The Heterogeneity of Prostate Cancer: A Practical Approach

Tolkach¹,

Kristiansen²

2018

Pathobiology

102

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“…We investigated if the detection of a positive cyst fluid methylation test was an independent predictor of grade of dysplasia when results were adjusted for other clinical factors (age, gender, cyst fluid appearance, cyst fluid DNA quantity, cyst size, cyst location, MPD dilatation, MPD communication, and mural nodule) used to evaluate patients (7,8). Multivariate analysis revealed that cyst fluid methylation remained an independent predictor of the grade of dysplasia high-grade dysplasia/invasive cancer vs. lower grades of dysplasia.…”

Section: Resultsmentioning

confidence: 99%

“…Solid-pseudopapillary neoplasms (SPN) have low malignant potential but require resection (6). Pancreatic cysts are currently evaluated using pancreatic imaging and any associated clinical features (7,8). Recent guidelines, often referred to as the “modified Sendai or Tanaka guidelines,” recommend that when an IPMN is diagnosed, only those suspected to have high-grade dysplasia or an associated invasive cancer need resection; IPMNs thought to have low- or intermediate-grade dysplasia are managed by surveillance (7).…”

Section: Introductionmentioning

confidence: 99%

Predicting the Grade of Dysplasia of Pancreatic Cystic Neoplasms Using Cyst Fluid DNA Methylation Markers

Hata

Molin

Hong

et al. 2017

Clinical Cancer Research

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Purpose Pancreatic cysts are common and pose diagnostic and management challenges. Pancreatic cyst fluid markers have the potential to aid in the management of cysts with concerning imaging findings. Our aim was to evaluate cyst fluid methylated DNA markers for their accuracy for predicting the histologic grade of neoplastic pancreatic cysts. Experimental Design Pancreatic cyst fluid samples from 183 patients (29 discovery, 154 validation) aspirated after surgical resection were analyzed for methylated DNA at selected genes (SOX17, BNIP3, FOXE1, PTCHD2, SLIT2, EYA4 and SFRP1) using methylation-specific droplet-digital PCR (dd-QMSP). Methylated DNA levels were evaluated for their accuracy at predicting the grade of dysplasia of the pancreatic cyst. Results All six markers evaluated in the validation set could accurately distinguish high-risk cystic neoplasms (with high-grade dysplasia and/or associated invasive cancer) from low-risk cysts (lower grades of dysplasia) with accuracies from 79.8 to 83.6%. Methylated SOX17 had the highest overall accuracy as a single marker (sensitivity, 78.4%; specificity, 85.6%; accuracy 83.6%, cut-off; 25 methylated DNA molecules/μL cyst fluid). The best four-gene combination had 84.3% sensitivity, 89.4% specificity and 88.0% accuracy at distinguishing cysts with high-grade dysplasia and/or invasive cancer from those without. All six markers were independent predictors of having invasive cancer/high-grade dysplasia after adjusting for clinical/imaging factors known to be associated with grade of dysplasia. The combination of methylated SOX17 with cytology better predicted neoplastic grade than cytology alone. Conclusion A panel of methylated gene markers quantified by dd-QMSP can be used to predict the grade of dysplasia of pancreatic cysts.

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“…Another recent report by Masica et al [21] has validated a model composed by the combination of clinical markers on a retrospective series of more than one thousand resected pancreatic cysts. The report reveals how larger cysts are associated with a higher risk of harboring malignancy.…”

Section: Discussionmentioning

confidence: 99%

“…The role of cyst size has been recently re-emphasized by a report involving a large cohort of surgically treated pancreatic cystic neoplasms (PCNs), showing how a diameter >4 cm is associated with malignant degeneration [21]. However, the actual role of the “size factor” remains controversial: while it is emphasized in most of the historical surgical series on PCN, the few longitudinal series available on undefined pancreatic cyst do not rely on it as a predictor of outcome [16, 22, 23].…”

Section: Introductionmentioning

confidence: 99%

Vanishing Pancreatic Cysts during Follow-Up: Another Step Towards De-Emphasizing Cyst Size as a Major Clinical Predictor of Malignancy

et al. 2017

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Introduction: In the management of pancreatic cystic neoplasms (PCN), size plays a crucial role as the expression of disease progression. While many evidences regarding the natural history of growing pancreatic cysts exist, almost no data are available regarding cysts with a reduction in size. Methods: Radiological and clinical data from patients of the dedicated pancreatic cysts outpatient clinic of the Department of General and Pancreatic Surgery, University of Verona Hospital were retrospectively reviewed. Patients diagnosed with PCNs reducing in size during follow-up were reviewed. Results: From a total of 3,146 patients, we identified 12 (0.38%) vanishing/reducing cysts without a history of pancreatitis. Most of them were presumed IPMN (66.6%). The median follow-up was 69 months and the median cyst’s size 30 mm (range 10–49). Most of the patients (75%) experienced a reduction in cyst size (median reduction of 8 mm, range 6–22) after a median time of 12 months (range 6–63), 3 patients experienced a complete disappearance of the cyst. Conclusion: Cyst size reduction during follow-up is a rare phenomenon of unknown explanation. It adds to the debate regarding the role of size as a clinical predictor whenever a definite diagnosis of a PCN cannot be reached.

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A novel approach for selecting combination clinical markers of pathology applied to a large retrospective cohort of surgically resected pancreatic cysts

Cited by 33 publications

References 22 publications

The Heterogeneity of Prostate Cancer: A Practical Approach

The Heterogeneity of Prostate Cancer: A Practical Approach

Predicting the Grade of Dysplasia of Pancreatic Cystic Neoplasms Using Cyst Fluid DNA Methylation Markers

Vanishing Pancreatic Cysts during Follow-Up: Another Step Towards De-Emphasizing Cyst Size as a Major Clinical Predictor of Malignancy

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