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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References

  1. 1.

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

  2. 2.

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

  3. 3.

    , & Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039–1049 (2014).

  4. 4.

    , , & Prevalence of incidental pancreatic cysts on 3 Tesla magnetic resonance. PLoS ONE 10, e0121317 (2015).

  5. 5.

    , , , & Cystic neoplasms of the pancreas. N. Engl. J. Med. 351, 1218–1226 (2004).

  6. 6.

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

  7. 7.

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

  8. 8.

    , , , & Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. Biomed. Res. Int. 2014, 474905 (2014).

  9. 9.

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

  10. 10.

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

  11. 11.

    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).

  12. 12.

    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).

  13. 13.

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

  14. 14.

    , , & Reflectance spectroscopy with polarized light: is it sensitive to cellular and nuclear morphology. Opt. Express. 5, 302–317 (1999).

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

    & 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).

  19. 19.

    & Mie theory interpretations of light scattering from intact cells. Opt. Lett. 30, 2442–2444 (2005).

  20. 20.

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

  21. 21.

    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).

  22. 22.

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

  23. 23.

    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).

  24. 24.

    , , , & Noninvasive identification of subcellular organization and nuclear morphology features associated with leukemic cells using light-scattering spectroscopy. J. Biomed. Opt. 16, 037007 (2011).

  25. 25.

    , & Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest. Endosc. 62, 383–389 (2005).

  26. 26.

    , & 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).

  27. 27.

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

  28. 28.

    Radiative Transfer (Dover, 1960).

  29. 29.

    , & When does the diffusion approximation fail to describe photon transport in random media? Phys. Rev. Lett. 64, 2647–2650 (1990).

  30. 30.

    , , & EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest. Endosc. 70, 710–723 (2009).

  31. 31.

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

  32. 32.

    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).

  33. 33.

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

  34. 34.

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

  35. 35.

    , , & Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am. J. Gastroenterol. 105, 2079–2084 (2010).

  36. 36.

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

  37. 37.

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

  38. 38.

    , & Endoscopic ultrasonography diagnosis of pancreatic cancer. Gastrointest. Endosc. Clin. N. Am. 5, 699–712 (1995).

  39. 39.

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

  40. 40.

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

  41. 41.

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

  42. 42.

    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).

  43. 43.

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

  44. 44.

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

  45. 45.

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

  46. 46.

    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).

  47. 47.

    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).

  48. 48.

    , , & Single-scattering spectroscopy for the endoscopic analysis of particle size in superficial layers of turbid media. Appl. Opt. 42, 4095–4101 (2003).

  49. 49.

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

  50. 50.

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

  51. 51.

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

  52. 52.

    et al. Dataset for ‘Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy’. figshare (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.

Author information

Author notes

    • Lei Zhang
    •  & Douglas K. Pleskow

    These authors contributed equally to this work.

Affiliations

  1. Center for Advanced Biomedical Imaging and Photonics, Department of Medicine and Department of Obstetrics, Gynecology and Reproductive Biology, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA

    • Lei Zhang
    • , Vladimir Turzhitsky
    • , Edward Vitkin
    • , Yuri Zakharov
    • , Umar Khan
    • , Irving Itzkan
    • , Le Qiu
    •  & Lev T. Perelman
  2. Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA

    • Douglas K. Pleskow
    • , Tyler M. Berzin
    • , Mandeep Sawhney
    • , Fen Wang
    • , Ram Chuttani
    •  & Lev T. Perelman
  3. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA

    • Eric U. Yee
    • , Shweta Shinagare
    •  & Jeffrey D. Goldsmith
  4. Division of Biostatistics and Biomathematics, Massachusetts General Hospital, Harvard University, Boston, Massachusetts 02114, USA

    • Saveli Goldberg
  5. Biological and Biomedical Sciences Program, Harvard University, Boston, Massachusetts 02115, USA

    • Lev T. Perelman

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Le Qiu or Lev T. Perelman.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary figure.

Videos

  1. 1.

    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.

  2. 2.

    Supplementary Video 2

    Same video recording as in Supplementary Video 1, with captions explaining the procedural steps, and with the video speed adjusted.

  3. 3.

    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.

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DOI

https://doi.org/10.1038/s41551-017-0040

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