Endosc Int Open 2015; 03(05): E479-E486
DOI: 10.1055/s-0034-1392016
Original article
© Georg Thieme Verlag KG Stuttgart · New York

# Managing incidental pancreatic cystic neoplasms with integrated molecular pathology is a cost-effective strategy

› Author Affiliations
Further Information

### Corresponding author

Ananya Das, MD
Arizona Center for Digestive Health
2680 S Valvista Drive, Suite #116
Gilbert, Arizona 85295
United States
Fax: +1-480-507-5677

### Publication History

submitted 13 February 2015

accepted after revision 02 March 2015

Publication Date:
26 June 2015 (online)

Background and study aims: Current guidelines recommend using endoscopic ultrasound (EUS), carcinoembryonic antigen (CEA) testing and cytology to manage incidental pancreatic cystic neoplasms (PCN); however, studies suggest a strategy including integrated molecular pathology (IMP) of cyst fluid may further aid in predicting risk of malignancy. Here, we evaluate several strategies for diagnosing and managing asymptomatic PCN using healthcare economic modeling.

Patients and methods: A third-party-payer perspective Markov decision model examined four management strategies in a hypothetical cohort of 1000 asymptomatic patients incidentally found to have a 3 cm solitary pancreatic cystic lesion. Strategy I used cross-sectional imaging, recommended surgery only if symptoms or risk factors emerged. Strategy II considered patients for resection without initial EUS. Strategy III (EUS + CEA + Cytology) referred only those with mucinous cysts (CEA > 192 ng/mL) for resection. Strategy IV implemented IMP; a commercially available panel provided a “Benign,” “Mucinous,” or “Aggressive” classification based on the level of mutational change in cyst fluid. “Benign” and “Mucinous” patients were followed with surveillance; “Aggressive” patients were referred for resection. Quality-adjusted life-years (QALY), relative risk with 95 %CI, Number Needed to Treat (NNT), and incremental cost-effectiveness ratios were calculated.

Results: Strategy IV provided the greatest increase in QALY at nearly identical cost to the cheapest approach, Strategy I. Relative risk of malignancy compared to the current standard of care and nearest competing strategy, Strategy III, was 0.18 (95 %CI 0.06 – 0.53) with an NNT of 56 (95 %CI 34 – 120).

Conclusions: Use of IMP was the most cost-effective strategy, supporting its routine clinical use.

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### Abbreviations

ACG: American College of Gastroenterology
ASA: American Society of Anesthesiology
CEA: carcinoembryonic antigen
CT: computed tomography
EUS: endoscopic ultrasound
FNA: fine needle aspiration
ICER: Incremental Cost-Effectiveness Ratio
IMP: integrated molecular pathology
INHB: Incremental Net Health Benefit
LOH: loss of heterozygosity
MCN: mucinous cystic neoplasms
NHB: Net Health Benefit
NNT: Number Needed to Treat
PCN: pancreatic cystic neoplasms
PFTG: PathFinder TG
SCN: serous cystic neoplasms
WTP: Willingness to Pay

### Introduction

In clinical practice, pancreatic cystic neoplasms (PCN) are being increasingly discovered on abdominal imaging studies performed for unrelated indications. Over 90 % of incidental PCNs can be broadly categorized as mucinous or non-mucinous [1] [2] Differentiating between these two cyst types is important because non-mucinous are commonly benign without risk of malignancy, while mucinous are considered to have an appreciable, although low, risk of malignant transformation [3]. Imaging and endoscopic features readily distinguish most serous cystadenomas (SCN) and main duct intraductal papillary mucinous neoplasms (IPMN) from other types of lesions. However, although side-branch IPMN and mucinous cystic neoplasms (MCN) are distinct histopathological entities, imaging alone often cannot definitively differentiate them.

The risk progression to cancer is a primary concern. Although surgery is effective in preventing cancer, many of PCNs are discovered in elderly patients with concomitant co-morbidities for whom aggressive prophylactic surgery is contraindicated [4]. The American College of Gastroenterology’s (ACG) 2007 practice guidelines for managing PCN recommend EUS-FNA and analysis of cyst fluid for tumor markers and cytology [5]. Per these guidelines, choosing surgery over surveillance should be based on whether the cyst is mucinous along with the presence or absence of additional risk factors (e. g., increasing cyst size, presence of mural nodules, solid component). In a previous analysis, we examined Strategies I – III, studied here, and found the most cost-effective approach to stratifying a patient’s risk of developing cancer from a cyst was to use EUS-FNA and cyst fluid analysis for CEA estimation [6].

Because morphological features of cysts lack strong predictive accuracy for malignancy, patients are often managed with surgery to mitigate the possibility of progression to cancer. Many resected cysts are benign, causing both unnecessary morbidity for patients and excessive costs to the healthcare system [4] [7]. Recent studies have shown that integrated molecular pathology (IMP) of patient cyst fluid may improve the ability to distinguish mucinous from non-mucinous cysts and is particularly helpful in predicting cysts’ malignant potential [8] [11].

IMP of cyst fluid for determining malignant potential was validated in the National Pancreatic Cyst Registry, which included clinical and molecular data from 492 patients who had IMP testing of pancreatic cyst fluid (PathFinder TG, RedPath Integrated Pathology, Pittsburgh, Pennsylvania, United States) as part of usual care. The registry findings support the use of IMP to augment first-line testing in determining a course of treatment based on the likelihood of developing malignancy. With a negative predictive value of 97.2 %, IMP can reliably identify cysts that will not develop malignancy, thereby reducing unnecessary surgeries and their related morbidity and mortality [12].

While data produced by IMP are promising, molecular analytical techniques are more expensive than other diagnostic modalities. In lieu of a prospective, randomized clinical trial, this study used healthcare economic modeling to evaluate the costs and benefits of different strategies for diagnosing and managing asymptomatic PCN.

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### Patients/material and methods

We simulated a hypothetical cohort of 1000 asymptomatic patients incidentally found to have a 3 cm solitary PCN on cross-sectional imaging. For baseline analysis, each patient was assumed to have an American Society of Anesthesiology (ASA) score of III. The model evaluated the impact of the cysts over the patients’ lifetime.

#### Model strategies

The model compared four management strategies ( [Fig. 1]):

• Wait & Watch, conservative: Cysts were followed using cross-sectional imaging and surgical consultation for resection of the cyst occurred only if the patient developed symptoms or high-risk morphological features.

• Resect if operable, aggressive: All patients were referred for surgical consultation for cyst resection. Operability was determined according to a surgical risk score as described below. No EUS-FNA was performed.

• EUS + CEA + Cytology, standard of care: After cross-sectional imaging, all patients underwent an EUS-guided FNA for differentiating between mucinous and non-mucinous cysts. Patients diagnosed with a mucinous cyst (e. g., via cytology or elevated CEA) were referred for surgical resection. Those with a non-mucinous diagnosis were followed in the model with periodic imaging surveillance as described below.

• EUS + CEA + Cytology + IMP: All patients initially underwent first-line testing, as in Strategy III, followed by molecular testing. PathFinder TG IMP incorporates first-line testing results with findings from molecular testing. Patients diagnosed as “Benign” via IMP were followed as in Strategy I, while those diagnosed as “Statistically Indolent” underwent more frequent surveillance. Those diagnosed as “Aggressive” were referred for surgical resection.

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#### Surveillance and surgery in the model

Using decision analysis software (TreeAge Pro, TreeAge Software, Inc, Williamstown, Massachusetts, United States), we built a hybrid model of a linear decision tree terminating in a Markov model. The Markov component of the model simulates the natural history of each patient's PCN using various health and disease states plus cancer related mortality. The varying malignant potential of mucinous cysts was considered. To account for age and gender-specific annual mortality from all other causes, the model incorporates US life table mortality rates.

SCN are typically identifiable on cross-sectional imaging [5], and these cysts were considered to have a benign course. Because mucinous cysts have varying malignant potential, the model incorporated both the probability of malignancy upon presentation and malignancy developing over time, and relevant performance characteristics for diagnosing mucinous vs. non-mucinous and malignant vs. benign ( [Table 1], Table S1).

Table 1

### Estimates for model variables (supporting references are noted in Table  S1 of the Supplement).

Model variable

Strategies that use this variable

Baseline value

Range for sensitivity analyses

Development of malignancy (%)

Cystic lesions that are non-mucinous (e. g., serous cystadenoma, pseudocyst)

All

30

10 – 60

Biological aggressiveness of mucinous cysts/ branch type IPMN (at presentation)

All

Benign

65

0 – 100

Borderline/indolent

20

0 – 100

Malignant

15

0 – 100

Probability of asymptomatic mucinous cyst or side-branch IPMN becoming symptomatic (annual)

All

Cyst is ≤ 3 cm

2

0 – 5

Cyst is > 3 cm

10

1 – 15

Probability of benign mucinous cystic lesion/branch type IPMN transitioning from benign to malignant (years)

Cyst is ≤ 3 cm

2.5

0 – 50

Cyst is > 3 cm

5

0 – 50

Probability of malignant cysts becoming symptomatic (annual)

25

0 – 100

Performance characteristics of diagnostic tests (%)

Differentiating mucinous from non-mucinous cysts

MRI/CT (sensitivity)

All

70

50 – 100

CEA + cytology (sensitivity)

III, IV

80

50 – 100

CEA + cytology (specificity)

III, IV

65

0 – 80

PathFinder TG + CEA + cytology (sensitivity)

IV

68

50 – 80

PathFinder TG + CEA + cytology (specificity)

IV

90

70 – 95

Distinguishing aggressive from non-aggressive cysts

PathFinder sensitivity

IV

82

70 – 90

PathFinder specificity

IV

85

70 – 90

Mortality and utility (used in calculating QALY)

Perioperative mortality (years)

3

1 – 15

Mortality from invasive malignant cysts (years)

10

0 – 5

Normal (%)

1.0

(N/A)

Incidental cyst (%)

1.0

0.75 – 1

Symptomatic cyst (%)

0.95

0.7 – 1

Postoperative state (%)

0.95

0.7 – 1

Early cancer (%)

0.9

0.68 – 1

0.5

0.38 – 1

Table 2

### Results (using baseline estimates of variables).

Strategy

Cost ($) Effectiveness (QALY) ICER ($/QALY) over Strategy I

I. Wait & watch

19 251

10.36

II. Resect if operable

32 393

9.95

– 32 054 (Dominated)

III. EUS-FNA + Cytology + CEA

25 841

11.22

6590 (Dominated)

IV. Integrated mutational profiling

19 373

12.33

62 (Preferred)

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#### Sensitivity analyses

One-way sensitivity analysis yielded interesting results: the variables expected to be most important did not significantly affect cost-effectiveness. Such variables included cost of EUS-FNA, cost of PathFinder TG assay, interval of surveillance by imaging, accuracy of cross-sectional imaging in differentiating mucinous from non-mucinous cysts, probability of malignant transformation of benign cysts, and perioperative mortality. When tested across the published range of estimates for percentage of PCNs that are mucinous and percentage of cysts that will progress to malignancy and cost of IMP, Strategy IV continued to be the most cost-effective approach (i. e., highest ICER).

In one-way sensitivity analyses, the surgical risk score did prove to be important in determining the cost and benefit of each management strategy. Between the maximum and minimum risk score, the most cost-effective strategy was Strategy IV (IMP) most often; however, when the risk score was above 8, the yield in effectiveness in terms of QALY was higher with Strategy I (Wait & Watch). Even using the lowest surgical risk score, Strategy II (Resect if operable) never resulted in the greatest number of QALY gained.

Because the cost of IMP and the performance characteristics of CEA analysis and IMP are likely to be inter-related determinants of the outcomes of the model, we looked at two-way sensitivity analyses by simultaneously varying these probabilities. [Fig.  2] and  [Fig. 3] show that even when these variables are varied over a broad range of estimates, IMP remains the preferred management method.

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#### Monte Carlo analysis

A second-order Monte Carlo analysis tests the robustness of the model when all variables randomly assume values across their plausible ranges. We performed this analysis with 1000 distinct hypothetical patients with cystic pancreatic disease using tracking variables to indicate whether surgery was performed or advanced malignancy occurred. [Table 3] shows the increase or decrease in per patient cost and QALY for each strategy according to whether the patient went to surgery, or did or did not develop malignant disease. In this Monte Carlo analysis, the number of surgical interventions performed in Strategies I, II, III, and IV were 135, 327, 247, and 127, respectively. Despite the drastic decrease in the number of surgeries from Strategy II to Strategy IV, 23 fewer advanced malignancies occurred in the latter arm while simultaneously reducing the average cost per patient by 11 910. The current standard of care, Strategy III, allowed advanced malignancy in 19 patients and cost 5553 more per patient than Strategy IV ([Table  3]). The number of unresectable malignant cystic tumors diagnosed under each strategy in this cohort was estimated at 18, 32, 19, and 9 for Strategies I, II, III, and IV, respectively.

Table 3

### Monte Carlo simulation of frequency of surgery and advanced malignancy with each strategy.

Surgery

Strategy

I Wait & watch

II Resect if operable

III EUS + CEA + cytology

IV Integrated molecular pathology

Patients (#)

Cost ($) QALY Patients (#) Cost ($)

QALY

Patients (#)

Cost ($) QALY Patients (#) Cost ($)

QALY

Yes

No[1]

135

42 830

14.53

327

40 000

12.69

247

41 574

13.21

127

45 537

13.6

No

No

847

13 150

9.77

641

22 596

7.92

734

16 518

10.64

864

14 118

12.22

Yes

18

109 339

5.41

32

106 130

6.43

19

111 232

8.24

9

113 652

4.77

Overall

1000

\$ 18 766

10.36

1000

30 876

9.95

1000

24 519

11.22

1000

18 966

12.3

1 The model assumes that surgery prevents progression to advanced malignancy.

In the Monte Carlo analysis, relative risk of unresectable pancreatic cyst-adenocarcinoma with Strategy IV (IMP) was 0.18 (95 %CI, 0.06 – 0.53) compared to the nearest competing approach, Strategy III. With this Monte Carlo simulation we arrived at a NNT of 56 (95 %CI 34 – 120) for Strategy IV. Finally, over a range of commonly used societal Willingness to Pay (WTP) thresholds, Strategy IV yields the highest NHB and Strategy II yields the lowest ([Fig.  4]).

The scatter plots of distribution of ICER of Strategy IV against Strategy III for the simulation trial in the hypothetical cohort show that in nearly 62 % of the simulation trials Strategy IV is dominant; however, in 9.4 % of simulations Strategy IV was inferior being more expensive and yielding a lower ICER. (Fig. 4S).

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### Discussion

Management of PCNs continues to pose a challenge for clinicians because the malignant potential for any given cyst is difficult to determine. Clinicians can choose surveillance, in which case progression to cancer is a concern, or they can choose surgery which has high associated morbidity. To address this dilemma, several guidelines for management of pancreatic cystic lesions have been published over the last decade [4] [5]. Unfortunately, given the limitations of current standard diagnostic modalities (e. g., imaging, CEA, cytology), there are many clinical scenarios that cannot be adequately addressed. For instance, guidelines recommend CEA testing to distinguish mucinous from non-mucinous lesions, but CEA has limited utility in assessing malignant potential; recent literature has shown that cysts with CEA lower than the threshold of 192 ng/mL may be malignant [23] [24]. Furthermore, the Sendai guidelines call for resection of mucinous cysts 3 cm or larger that have concurrent “worrisome features.” [4]. However, numerous reports document that cysts smaller than 3 cm (or even 1 cm) may harbor malignancy [23] [24] [25] [26] [27]. To address imaging’s limitations, the 2012 Sendai guidelines suggest surveillance intervals ranging from every 2 years for cysts < 1 cm to every 3 – 6 months for cysts 2 cm or larger. Similarly, the most recent ACG guidelines (2007) recommend surveillance for cysts strongly suspected to be benign and surgical resection for those strongly suspected to be malignant, but they do not provide specific parameters [5]. In the context of these limitations there is inherent uncertainty in choosing a particular strategy, and scant information exists regarding the cost-effectiveness of different management strategies in this clinical scenario. Given that a controlled, randomized study examining different strategies of managing PCNs with long-term follow-up is unlikely to be available for the future, a practical way to develop management recommendations is to conduct healthcare economic modeling based on available clinical data.

In a previous analysis, we showed that EUS-FNA with cyst fluid analysis for CEA level was the most cost-effective strategy for managing incidental PCNs. This study extended that previous work by adding a management strategy, Strategy IV, which incorporated IMP to determine the malignant potential of cysts; only those patients with “Aggressive” molecular features were referred for surgery, while those with “Benign” or “Statistically Indolent” results were followed with surveillance at progressively longer intervals. Our primary finding was that Strategy IV was very cost-effective compared to the other strategies and provided the greatest increase in QALY. The increase of 2.38 QALY between Strategy II and Strategy IV compares favorably to gains observed in other clinical scenarios, such as use of ablation to eradicate high grade dysplasia in Barrett’s esophagus (3.24 QALY increase) [28].

In addition to these findings, our simulation also provided the NNT, a key parameter in assessing cost-effectiveness of management strategies. In this model, PathFinder TG had an NNT of 56, representing the number of patients that needed IMP to prevent advanced malignancy in one patient. As a comparison, the current standard of care for managing PCNs, Strategy III, has an NNT of 83, and ablation of non-dysplastic Barrett’s esophagus, an emerging practice, has an NNT ranging from 23 – 250 [6] [29]. These data further reinforce the cost-effectiveness of IMP.

Our analyses indicate that the IMP strategy achieves its cost-effectiveness by limiting unnecessary surgery while maintaining the lowest rate of advanced malignancy, thus showing how accurate prediction of malignant potential resolves the dilemma between preventing cancer and performing unnecessary surgery. The high expense of surgery explains why the model was not sensitive to seemingly important variables such as cost of cross-sectional imaging or the performance characteristics of IMP; the cost of PathFinder TG testing is greatly exceeded by the expense of even a few unnecessary surgeries.

We acknowledge several limitations of this study, many of which are inherent to any healthcare economic model. Literature on the performance characteristics of current standard diagnostic modalities is abundant; however, as with any newer diagnostic test, available evidence regarding the performance characteristics of IMP is limited. Some of the published studies are limited by sample size and lack of long-term follow-up data. To account for some of the shortcomings of these data and to intentionally bias the model against IMP-based prediction of malignant potential, we used the low end of published estimates of diagnostic accuracy for PathFinder TG for all analyses. Data from the National Pancreatic Cyst Registry, which were not published prior to our search cutoff of May 2012, provide evidence that the estimates used in our model were indeed conservative. IMP sensitivity was over 83 %, and specificity was over 90 %. The accuracy of IMP was 90 % [12].

Because natural history of PCN are not fully known, the model needed to make assumptions about some variables in which scientifically sound data are lacking; thus, in some cases such assumptions were based on expert opinion [6]. To compensate for this, we used sophisticated techniques of uncertainty analysis, such as second-order Monte Carlo analysis and simulation trials over a wide but biologically plausible range of estimates of important variables to confirm validity of the conclusions. We also assumed low surgical cost and complication rates further biasing the model against IMP. One important limitation is that the surgical risk score developed for this analysis has not undergone formal clinical validation. Another limitation of this study is that it did account for all PCNs. In particular, main duct IPMNs including mixed type (both main and branch duct involvement) were not included because their management would likely involve a different diagnostic algorithm based on endoscopic retrograde cholangiopancreatography, the gold standard for diagnosis of main duct IPMN [30]. Also, we did not consider postoperative morbidity and complications related to EUS-FNA procedures. Finally, only direct costs were taken into account.

While current first-line diagnostic tests have lower cost and wider availability, they cannot provide consistent, meaningful prediction of malignant potential [23] [24]. Nevertheless, standard clinical management of patients with PCN relies on these first-line tests, the results of which are reflected in Strategy III. Even with the model being heavily biased against IMP, we found that using IMP to predict malignant potential is superior to Strategy III and represents the most cost-effective strategy for managing PCN. These results demonstrate that a reasonably accurate risk-stratification tool (e. g., IMP) provides a significant benefit in reducing cost and improving QALY for pancreatic cyst patients.

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Competing interests: Ananya Das, M.D.: Research support from Redpath Integrated Pathology for pancreatic cyst healthcare economics prolect and Barrett’s esophagus healthcare economics project; Consultant, Boston scientific, Inc., Natick, Massachusetts, USA; Consultant Endostim, Inc., St Louis, MI. William Brugge, M.D.: Research grants from RedPath Integrated Pathology and Asuragen, Girish Mishra, M.D.: Consultant for Novartis Pharmaceuticals, Cook Endoscopy, Pentax Medical. Dennis Smith: Employee, board member, investor, and shareholder at RedPath, Mankanwal Sachdev, M.D.: No conflicts to report. Eric Ellsworth: Employee and shareholder of RedPath.

### Acknowledgments

Rebecca J. Palmer, PhD, funded by RedPath Integrated Pathology (Pittsburgh, Pennsylvania, United States) assisted in the preparation of this manuscript. RedPath provided personnel support to assist with data analysis and interpretation and manuscript preparation.

### Corresponding author

Ananya Das, MD
Arizona Center for Digestive Health
2680 S Valvista Drive, Suite #116
Gilbert, Arizona 85295
United States
Fax: +1-480-507-5677