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Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy

Abstract

Pancreatic cancers are usually detected at an advanced stage and have poor prognosis. About one-fifth of these arise from pancreatic cystic lesions. Yet not all lesions are precancerous, and imaging tools lack adequate accuracy for distinguishing precancerous from benign cysts. Therefore, decisions on surgical resection usually rely on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Unfortunately, cyst fluid often contains few cells, and fluid chemical analysis lacks accuracy—which has dire consequences, including unnecessary pancreatic surgery for benign cysts and the development of cancer. Here, we report an optical spectroscopic technique, based on a spatial gating fibre-optic probe, that predicts the malignant potential of pancreatic cystic lesions during routine diagnostic EUS-FNA procedures. In a double-blind prospective study in 25 patients, with 14 cysts measured in vivo and 13 postoperatively, the technique achieved an overall accuracy of 95%, with a 95% confidence interval of 78–99%, in cysts with definitive diagnosis.

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Figure 1: Ex vivo optical spectroscopic differentiation of cystic neoplasms.
Figure 2: In vivo spatial gating fibre optic probe for use with EUS-FNA.
Figure 3: In vivo measurements during the endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) procedure.
Figure 4: In vivo optical spectroscopic differentiation of cystic neoplasms in 14 subjects.

References

  1. 1

    Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Brand, R. E. et al. Advances in counselling and surveillance patients at risk for pancreatic cancer. Gut 56, 1460–1469 (2007).

    Article  Google Scholar 

  3. 3

    Ryan, D. P., Hong, T. S. & Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039–1049 (2014).

    CAS  Article  Google Scholar 

  4. 4

    de Oliveira, P. B., Puchnick, A., Szejnfeld, J. & Goldman, S. M. Prevalence of incidental pancreatic cysts on 3 Tesla magnetic resonance. PLoS ONE 10, e0121317 (2015).

    Article  Google Scholar 

  5. 5

    Brugge, W. R., Lauwers, G. Y., Sahani, D., Fernandez-del Castillo, C. & Warshaw, A. L. Cystic neoplasms of the pancreas. N. Engl. J. Med. 351, 1218–1226 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Brugge, W. R. et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 126, 1330–1336 (2004).

    Article  Google Scholar 

  7. 7

    Cizginer, S. et al. Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts. Pancreas 40, 1024–1028 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Distler, M., Aust, D., Weitz, J., Pilarsky, C. & Grützmann, R. Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. Biomed. Res. Int. 2014, 474905 (2014).

    CAS  Article  Google Scholar 

  9. 9

    Singh, M. & Maitra, A. Precursor lesions of pancreatic cancer: molecular pathology and clinical implications. Pancreatology 7, 9–19 (2007).

    CAS  Article  Google Scholar 

  10. 10

    Birkmeyer, J. D. et al. Hospital volume and surgical mortality in the United States. N. Engl. J. Med. 346, 1128–1137 (2002).

    Article  Google Scholar 

  11. 11

    Kosmahl, M. et al. Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows. Arch. 445, 168–178 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Perelman, L. T. et al. Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution. Phys. Rev. Lett. 80, 627–630 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Qiu, L. et al. Multispectral scanning during endoscopy guides biopsy of dysplasia in Barrett’s esophagus. Nat. Med. 16, 603–606 (2010).

    CAS  Article  Google Scholar 

  14. 14

    Sokolov, K., Drezek, R., Gossage, K. & Richards-Kortum, R. Reflectance spectroscopy with polarized light: is it sensitive to cellular and nuclear morphology. Opt. Express. 5, 302–317 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Yu, C. C. et al. Assessing epithelial cell nuclear morphology by using azimuthal light scattering spectroscopy. Opt. Lett. 31, 3119–3121 (2006).

    Article  Google Scholar 

  16. 16

    Terry, N. G. et al. Detection of dysplasia in Barrett's esophagus with in vivo depth-resolved nuclear morphology measurements. Gastroenterology 140, 42–50 (2011).

    Article  Google Scholar 

  17. 17

    Qiu, L. et al. Spectral imaging with scattered light: from early cancer detection to cell biology. IEEE. J. Sel. Top. Quant. Elect. 18, 1073–1083 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Wax, A. & Chalut, K. Nuclear morphology measurements with angle-resolved low coherence interferometry for application to cell biology and early cancer detection. Anal. Cell. Pathol. 34, 207–222 (2011).

    Article  Google Scholar 

  19. 19

    Wilson, J. D. & Foster, T. H. Mie theory interpretations of light scattering from intact cells. Opt. Lett. 30, 2442–2444 (2005).

    Article  Google Scholar 

  20. 20

    Schuele, G. et al. Optical spectroscopy noninvasively monitors response of organelles to cellular stress. J. Biomed. Opt. 10, 051404 (2005).

    Article  Google Scholar 

  21. 21

    Itzkan, I. et al. Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels. Proc. Natl Acad. Sci. USA 104, 17255–17260 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Mourant, J. R. et al. Light scattering from cells: the contribution of the nucleus and the effects of proliferative status. J. Biomed. Opt. 5, 131–137 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Drezek, R. et al. Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture. J. Biomed. Opt. 8, 7–16 (2003).

    Article  Google Scholar 

  24. 24

    Hsiao, A., Hunter, M., Greiner, C., Gupta, S. & Georgakoudi, I. Noninvasive identification of subcellular organization and nuclear morphology features associated with leukemic cells using light-scattering spectroscopy. J. Biomed. Opt. 16, 037007 (2011).

    Article  Google Scholar 

  25. 25

    van der Waaij, L. A., van Dullemen, H. M. & Porte, R. J. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest. Endosc. 62, 383–389 (2005).

    Article  Google Scholar 

  26. 26

    Farrell, T. J., Patterson, M. S. & Wilson, B. A diffusion theory model of spatially resolved, steady-state diffuse reflectance for the noninvasive determination of tissue optical properties in vivo. Med. Phys. 19, 879–888 (1992).

    CAS  Article  Google Scholar 

  27. 27

    Vitkin, E. et al. Photon diffusion near the point-of-entry in anisotropically scattering turbid media. Nat. Commun. 2, 587 (2011).

    Article  Google Scholar 

  28. 28

    Chandrasekhar, S. Radiative Transfer (Dover, 1960).

    Google Scholar 

  29. 29

    Yoo, K. M., Liu, F. & Alfano, R. R. When does the diffusion approximation fail to describe photon transport in random media? Phys. Rev. Lett. 64, 2647–2650 (1990).

    CAS  Article  Google Scholar 

  30. 30

    DeWitt, J., McGreevy, K., Schmidt, C. M. & Brugge, W. R. EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest. Endosc. 70, 710–723 (2009).

    Article  Google Scholar 

  31. 31

    Simons, J. P. et al. Malignant intraductal papillary mucinous neoplasm: are we doing the right thing? J. Surg. Res. 167, 251–257 (2011).

    Article  Google Scholar 

  32. 32

    Oguz, D. et al. Accuracy of endoscopic ultrasound-guided fine needle aspiration cytology on the differentiation of malignant and benign pancreatic cystic lesions: a single-center experience. J. Dig. Dis. 14, 132–139 (2013).

    Article  Google Scholar 

  33. 33

    Baker, M. S. et al. Pancreatic cystic neuroendocrine tumors: preoperative diagnosis with endoscopic ultrasound and fine-needle immunocytology. J. Gastrointest. Surg. 12, 450–456 (2008).

    Article  Google Scholar 

  34. 34

    Winter, J. M. et al. Periampullary and pancreatic incidentaloma: a single institution's experience with an increasingly common diagnosis. Ann. Surg. 243, 673–683 (2006).

    Article  Google Scholar 

  35. 35

    Lee, K. S., Sekhar, A., Rofsky, N. M. & Pedrosa, I. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am. J. Gastroenterol. 105, 2079–2084 (2010).

    Article  Google Scholar 

  36. 36

    Laffan, T. A. et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am. J. Roentgenol. 191, 802–807 (2008).

    Article  Google Scholar 

  37. 37

    Boot, C. A review of pancreatic cyst fluid analysis in the differential diagnosis of pancreatic cyst lesions. Ann. Clin. Biochem. 51, 151–166 (2014).

    Article  Google Scholar 

  38. 38

    Yasuda, K., Mukai, H. & Nakajima, M. Endoscopic ultrasonography diagnosis of pancreatic cancer. Gastrointest. Endosc. Clin. N. Am. 5, 699–712 (1995).

    CAS  Article  Google Scholar 

  39. 39

    DeWitt, J. et al. Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer. Ann. Intern. Med. 141, 753–763 (2004).

    Article  Google Scholar 

  40. 40

    Park, W. G. et al. Diagnostic performance of cyst fluid carcinoembryonic antigen and amylase in histologically confirmed pancreatic cysts. Pancreas 40, 42–45 (2011).

    CAS  Article  Google Scholar 

  41. 41

    Steinberg, W. The clinical utility of the CA 19-9 tumor-associated antigen. Am. J. Gastroenterol. 85, 350–355 (1990).

    CAS  PubMed  Google Scholar 

  42. 42

    Kim, J. E. et al. Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population. J. Gastroenterol. Hepatol. 19, 182–186 (2004).

    Article  Google Scholar 

  43. 43

    Khalid, A. et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest. Endosc. 69, 1095–1102 (2009).

    Article  Google Scholar 

  44. 44

    Bick, B. L. et al. The string sign for diagnosis of mucinous pancreatic cysts. Endoscopy 47, 626–631 (2015).

    Article  Google Scholar 

  45. 45

    Wu, J. et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci. Transl. Med. 3, 92ra66 (2011).

    CAS  Article  Google Scholar 

  46. 46

    Amato, E. et al. Targeted next generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J. Pathol. 233, 217–227 (2014).

    CAS  Article  Google Scholar 

  47. 47

    Wu, J. et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc. Natl Acad. Sci. USA. 108, 21188–21193 (2011).

    CAS  Article  Google Scholar 

  48. 48

    Amelink, A., Bard, M. P., Burgers, S. A. & Sterenborg, H. J. Single-scattering spectroscopy for the endoscopic analysis of particle size in superficial layers of turbid media. Appl. Opt. 42, 4095–4101 (2003).

    Article  Google Scholar 

  49. 49

    Mutyal, N. N. et al. In vivo risk analysis of pancreatic cancer through optical characterization of duodenal mucosa. Pancreas 44, 735–741 (2015).

    Article  Google Scholar 

  50. 50

    Zonios, G. et al. Diffuse reflectance spectroscopy of human adenomatous colon polyps in vivo. Appl. Opt. 38, 6628–6637 (1999).

    CAS  Article  Google Scholar 

  51. 51

    Newcombe, R. G. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat. Med. 17, 857–872 (1998).

    CAS  Article  Google Scholar 

  52. 52

    Zhang, L. et al. Dataset for ‘Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy’. figshare http://dx.doi.org/10.6084/m9.figshare.4496039 (2017).

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Acknowledgements

We thank Y. Li for help in data acquisition. This work was supported by US National Institutes of Health grants R01 EB003472 and R01 CA205431 and US National Science Foundation grants CBET-1402926 and CBET-1605116.

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Authors

Contributions

L.Q., D.K.P. and L.T.P. conceived the method and initiated the project; L.Q. and L.T.P. supervised the project; L.Q., L.Z., U.K. and Y.Z. constructed the system; D.K.P., R.C., M.S. and T.M.B. performed clinical procedures; L.Z., Y.Z., U.K. and L.Q. performed measurements; E.U.Y., S.S. and J.D.G. evaluated the histology specimens; E.V. performed the data analysis; L.Z., E.U.Y., V.T., J.D.G., F.W., L.Q. and L.T.P. evaluated the method; S.G. performed statistical analysis; V.T., I.I., T.M.B., L.Z. and L.Q. contributed to the writing of the manuscript; L.T.P. wrote the manuscript.

Corresponding authors

Correspondence to Le Qiu or Lev T. Perelman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figure. (PDF 246 kb)

Supplementary Video 1

Video recording of an endoscopic ultrasound-guided fine-needle-aspiration procedure in a pancreatic cyst, combined with light scattering spectroscopic (LSS) measurements. The overall duration of the LSS data collection is less than 1.5 minutes. (AVI 16649 kb)

Supplementary Video 2

Same video recording as in Supplementary Video 1, with captions explaining the procedural steps, and with the video speed adjusted. (AVI 15042 kb)

Supplementary Video 3

Operation of the probe-latching mechanism, extending the probe tip from the needle and retracting it into the needle. The position-locking button is also shown. (AVI 7221 kb)

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Zhang, L., Pleskow, D., Turzhitsky, V. et al. Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy. Nat Biomed Eng 1, 0040 (2017). https://doi.org/10.1038/s41551-017-0040

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