Abstract

Using the hamster cheek pouch carcinogenesis model, we explore which fluorescence excitation wavelengths are useful for the detection of neoplasia. 42 hamsters were treated with DMBA to induce carcinogenesis, and 20 control animals were treated only with mineral oil. Fluorescence excitation emission matrices were measured from the cheek pouches of the hamsters weekly. Results showed increased fluorescence near 350–370 nm and 410 nm excitation and decreased fluorescence near 450–470 nm excitation with neoplasia. The optimal diagnostic excitation wavelengths identified using this model - 350–370 nm excitation and 400–450 nm excitation - are similar to those identified for detection of human oral cavity neoplasia.

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    [CrossRef]
  2. G.A. Wagnieres, W.M. Star, and B.C. Wilson, "In vivo fluorescence spectroscopy and imaging for oncological applications," Photochemistry and Photobiology 68, 603-32 (1998).
    [PubMed]
  3. H. Stepp, R. Sroka, R. Baumgartner, "Fluorescence endoscopy of gastrointestinal diseases: basic principles, techniques, and clinical experience," Endoscopy 30, 379-86 (1998).
    [CrossRef] [PubMed]
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    [PubMed]
  5. A.R.Gillenwater, R. Jacob, R. Ganeshappa, B. Kemp, A.K. El-Naggar, J.L. Palmer, G. Clayman, M.F. Mitchell, and R. Richards-Kortum, "Noninvasive diagnosis of oral neoplasia based on fluorescence spectroscopy and native tissue autofluorescence," Archives of Otolaryngology - Head and Neck Surgery 124, 1251-1258 (1998).
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    [CrossRef] [PubMed]
  7. D.R. Ingrams, J.K. Dhingra, K. Roy, D.F. Perrault Jr., I.D. Bottrill, S. Kabani, E.E. Rebeiz, M.M. Pankratov, S.M. Shapshay, R. Manoharan, I. Itzkan, and M.S. Feld, "Autofluorescence characteristics of oral mucosa," Head & Neck 19, 27-32 (1997).
    [CrossRef] [PubMed]
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    [CrossRef]
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    [CrossRef]
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  13. A. Zuluaga, U. Utzinger, A. Durkin, H. Fuchs, A. Gillenwater, R. Jacob, B. Kemp, J. Fan, R. Richards-Kortum, "Fluorescence EEMs of Human Tissue: A System for in vivo Measurements and Method of Data Analysis," Applied Spectroscopy 53, 302-310 (1999).
    [CrossRef]
  14. R.A. Zangaro, L. Silveira, R. Manoharan, G. Zonios, I. Itzkan, R. Dasari, J.C. Van Dam, M.S. Feld, "Rapid multiexcitation fluorescence spectroscopy system for in vivo tissue diagnosis," Applied Optics 35, 5211- 5219, (1996).
    [CrossRef] [PubMed]
  15. J.A. Zuclich, T. Shimada, T.R. Loree, I. Bigio, K. Strobl, Shuming Nie, "Rapid noninvasive optical characterization of the human lens," Lasers in the Life Sciences, 6, 39-53 (1994).
  16. I.M. Warner, G.D. Christian, E.R. Davidson, J.B. Callis, "Analysis of multicomponent fluorescence data," Analytical Chemistry 49, 564-573 (1977).
    [CrossRef]
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    [CrossRef] [PubMed]
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    [PubMed]
  19. J.K. Dhingra, X. Zahng, K. McMillan, S. Kabani, R. Manoharan, I. Itzkan, M.S. Feld, S.M. Sharpshay, "Diagnosis of head and neck precancerous lesions in an animal model using fluorescence spectroscopy," Laryngoscope 108, 471-475 (1998).
    [CrossRef] [PubMed]
  20. J.K. Dhingra, D.F. Perrault, K. McMillan, E.E. Rebeiz, S. Kabani, R. Manoharan, I. Itzkan, M.S. Feld, S.M. Shapshay, "Early diagnosis of upper aerodigestive tract cancer by autofluorescence," Arch Otolaryngol Head Neck Surg 122, 1181-1186 (1996).
    [CrossRef] [PubMed]
  21. C.T. Chen, H.K. Chiang, S.N. Chow, C.Y. Wang, Y.S. Lee, J.C. Tsai, C.P. Chiang, "Autofluorescence in normal and malignant human oral tissues and in DMBA-induced hamster buccal pouch carcinogenesis," Journal of Oral Pathology & Medicine 27, 470-474 (1998).
    [CrossRef] [PubMed]
  22. D.L. Heintzelman, U. Utzinger, H. Fuchs, A. Zuluaga, K. Gossage, A.M. Gillenwater, R. Jacob, B. Kemp, R. Richards-Kortum, "Optimal Excitation Wavelengths for In Vivo Detection of Oral Neoplasia Using Fluorescence Spectroscopy," Photochemistry and Photobiology, in press (2000).
  23. L. Coghlan, U. Utzinger, R. Richards-Kortum, C. Brookner, A. Zuluaga, I. Gimenez-Conti, M. Follen, "Fluorescence Spectroscopy of Epithelial Tissue Throughout the Dysplasia-Carcinoma Sequence in an Animal Model: Spectroscopic Changes Precede Morphologic Changes," Lasers in Surgery and Medicine submitted (2000).
  24. W.R. Dillon, M. Goldstein, Multivariate Analysis Methods and Applications, (John Wiley & Sons, 1984), Chap. 10.
  25. B. Chance, "Optical Method," Annu. Rev. Biophys. Biophys. Chem. 20, 1-28 (1991).
    [CrossRef] [PubMed]

Other

E. Sevick-Muraca and R. Richards-Kortum, "Quantitative optical spectroscopy for tissue diagnosis," Ann Rev Phys Chem 47, 555-606 (1996).
[CrossRef]

G.A. Wagnieres, W.M. Star, and B.C. Wilson, "In vivo fluorescence spectroscopy and imaging for oncological applications," Photochemistry and Photobiology 68, 603-32 (1998).
[PubMed]

H. Stepp, R. Sroka, R. Baumgartner, "Fluorescence endoscopy of gastrointestinal diseases: basic principles, techniques, and clinical experience," Endoscopy 30, 379-86 (1998).
[CrossRef] [PubMed]

S.P. Schantz, V. Kolli, H.E. Savage, G. Yu, J.P. Shah, D.E. Harris, A. Katz, R.R. Alfan, and A.G. Huvos "In vivo native cellular fluorescence and histological characteristics of head and neck cancer," Clinical Cancer Research 4, 1177-1182 (1998).
[PubMed]

A.R.Gillenwater, R. Jacob, R. Ganeshappa, B. Kemp, A.K. El-Naggar, J.L. Palmer, G. Clayman, M.F. Mitchell, and R. Richards-Kortum, "Noninvasive diagnosis of oral neoplasia based on fluorescence spectroscopy and native tissue autofluorescence," Archives of Otolaryngology - Head and Neck Surgery 124, 1251-1258 (1998).

V. Kolli, H.E. Savage, T.J. Yao, and S.P. Schantz, "Native cellular fluorescence of neoplastic upper aerodigestive mucosa," Arch. Otolaryng. Head Neck Surg. 121, 1287-92 (1995).
[CrossRef] [PubMed]

D.R. Ingrams, J.K. Dhingra, K. Roy, D.F. Perrault Jr., I.D. Bottrill, S. Kabani, E.E. Rebeiz, M.M. Pankratov, S.M. Shapshay, R. Manoharan, I. Itzkan, and M.S. Feld, "Autofluorescence characteristics of oral mucosa," Head & Neck 19, 27-32 (1997).
[CrossRef] [PubMed]

N. Ramanujam, M. Follen-Mitchell, A. Mahadevan-Jansen, S. Thomsen, G. Staerkel, A. Malpica, T. Wright, N. Atkinson and R. Richards-Kortum, "Cervical precancer detection using multivariate statistical algorithm based on laser-induced fluorescence spectra at multiple excitation wavelengths," Photochemistry and Photobiology 64, 720-735 (1996).
[CrossRef] [PubMed]

A. Agrawal, U. Utzinger, C. Brookner, C. Pitris, M. F. Mitchell, R. Richards-Kortum, "Fluorescence spectroscopy of the cervix: influence of acetic acid, cervical mucus, and vaginal medications," Lasers in Surgery & Medicine, 25, 237-49 (1999).
[CrossRef]

K. Schomacker, J. Frisoli, C. Compton, T. Flotte, J. Richter, N. Nishioka and T. Deutsch, "Ultraviolet laser-induced fluorescence of colonic tissue: basic biology and diagnostic potential," Lasers in Surgery & Medicine, 12, 63-78 (1992).
[CrossRef]

T. D.Wang, JM. Crawford, M.S. Feld, Y. Wang, I. Itzkan, J. Van Dam, "In vivo identification of colonic dysplasia using fluorescence endoscopic imaging," Gastrointestinal Endoscopy, 49(4 Pt 1), 447-55 (1999).
[CrossRef]

M.A. Mycek, K.T. Schomacker, N.S. Nishioka, "Colonic polyp differentiation using time-resolved autofluorescence spectroscopy," Gastrointestinal Endoscopy 48, 390-4 (1998).
[CrossRef] [PubMed]

A. Zuluaga, U. Utzinger, A. Durkin, H. Fuchs, A. Gillenwater, R. Jacob, B. Kemp, J. Fan, R. Richards-Kortum, "Fluorescence EEMs of Human Tissue: A System for in vivo Measurements and Method of Data Analysis," Applied Spectroscopy 53, 302-310 (1999).
[CrossRef]

R.A. Zangaro, L. Silveira, R. Manoharan, G. Zonios, I. Itzkan, R. Dasari, J.C. Van Dam, M.S. Feld, "Rapid multiexcitation fluorescence spectroscopy system for in vivo tissue diagnosis," Applied Optics 35, 5211- 5219, (1996).
[CrossRef] [PubMed]

J.A. Zuclich, T. Shimada, T.R. Loree, I. Bigio, K. Strobl, Shuming Nie, "Rapid noninvasive optical characterization of the human lens," Lasers in the Life Sciences, 6, 39-53 (1994).

I.M. Warner, G.D. Christian, E.R. Davidson, J.B. Callis, "Analysis of multicomponent fluorescence data," Analytical Chemistry 49, 564-573 (1977).
[CrossRef]

J.C. Zenklusen, S.L. Stockman, S.M. Fischer, C.J. Conti, I.B. Gimenez-Conti, "Transforming growth factor-beta 1 expression in Syrian hamster cheek pouch carcinogenesis," Molecular Carcinogenesis 9, 10- 16 (1994).
[CrossRef] [PubMed]

I.B. Gimenez-Conti, D.M. Shin, A.B. Bianchi, D.R. Roop, W.K. Hong, C.J. Conti, T.J. Slaga, "Changes in keratin expression during 7, 12-dimethylbenz[a]anthracene-induced hamster cheek pouch carcinogenesis," Cancer Res 50, 4441-4445 (1990).
[PubMed]

J.K. Dhingra, X. Zahng, K. McMillan, S. Kabani, R. Manoharan, I. Itzkan, M.S. Feld, S.M. Sharpshay, "Diagnosis of head and neck precancerous lesions in an animal model using fluorescence spectroscopy," Laryngoscope 108, 471-475 (1998).
[CrossRef] [PubMed]

J.K. Dhingra, D.F. Perrault, K. McMillan, E.E. Rebeiz, S. Kabani, R. Manoharan, I. Itzkan, M.S. Feld, S.M. Shapshay, "Early diagnosis of upper aerodigestive tract cancer by autofluorescence," Arch Otolaryngol Head Neck Surg 122, 1181-1186 (1996).
[CrossRef] [PubMed]

C.T. Chen, H.K. Chiang, S.N. Chow, C.Y. Wang, Y.S. Lee, J.C. Tsai, C.P. Chiang, "Autofluorescence in normal and malignant human oral tissues and in DMBA-induced hamster buccal pouch carcinogenesis," Journal of Oral Pathology & Medicine 27, 470-474 (1998).
[CrossRef] [PubMed]

D.L. Heintzelman, U. Utzinger, H. Fuchs, A. Zuluaga, K. Gossage, A.M. Gillenwater, R. Jacob, B. Kemp, R. Richards-Kortum, "Optimal Excitation Wavelengths for In Vivo Detection of Oral Neoplasia Using Fluorescence Spectroscopy," Photochemistry and Photobiology, in press (2000).

L. Coghlan, U. Utzinger, R. Richards-Kortum, C. Brookner, A. Zuluaga, I. Gimenez-Conti, M. Follen, "Fluorescence Spectroscopy of Epithelial Tissue Throughout the Dysplasia-Carcinoma Sequence in an Animal Model: Spectroscopic Changes Precede Morphologic Changes," Lasers in Surgery and Medicine submitted (2000).

W.R. Dillon, M. Goldstein, Multivariate Analysis Methods and Applications, (John Wiley & Sons, 1984), Chap. 10.

B. Chance, "Optical Method," Annu. Rev. Biophys. Biophys. Chem. 20, 1-28 (1991).
[CrossRef] [PubMed]

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Figures (6)

Fig. 1.
Fig. 1.

Block diagram of system used to measure fluorescence EEMs.

Table 1a.
Table 1a.

Study design for the DMBA treated and control group animals. Colored boxes indicate measurement events. Histopathologic diagnoses are shown with abbreviations, where N=normal, INF=inflammation, U=ulceration, H=hyperplasia, I=grade I dysplasia, II=grade II dysplasia, III=grade III dysplasia, CIS=carcinoma in situ, and SCC=squamous cell carcinoma. Discrepant diagnoses are indicated with D. Yellow shaded boxes indicate those non-neoplastic measurements used in algorithm development; orange shaded boxes indicate those neoplastic measurements used in algorithm development; pink shaded boxes indicate those measurements with fluorescence EEMs discarded during data review. Light blue shaded boxes indicate measurement where diagnosis was undetermined and therefore not used for algorithm development.

Table 1b.
Table 1b.

Table 1, part 2. Study design for the DMBA treated and control group animals. Colored boxes indicate measurement events. Histopathologic diagnoses are shown with abbreviations, where N=normal, INF=inflammation, U=ulceration, H=hyperplasia, I=grade I dysplasia, II=grade II dysplasia, III=grade III dysplasia, CIS=carcinoma in situ, and SCC=squamous cell carcinoma. Discrepant diagnoses are indicated with D. Yellow shaded boxes indicate those non-neoplastic measurements used in algorithm development; orange shaded boxes indicate those neoplastic measurements used in algorithm development; pink shaded boxes indicate those measurements with fluorescence EEMs discarded during data review. Light blue shaded boxes indicate measurement where diagnosis was undetermined and therefore not used for algorithm development.

Fig. 2.
Fig. 2.

Fluorescence EEMs of (left) non-neoplastic and (right) neoplastic hamster cheek pouch.

Fig. 3.
Fig. 3.

Video illustrating fluorescence EEMs each week for a hamster treated with DMBA. Biopsy at week 10 showed grade II dysplasia and histology at week 17 showed squamous cell carcinoma (1.459 KB).

Fig. 4.
Fig. 4.

Histograms depicting the frequency of occurrence of each excitation wavelength in the 25 top performing combinations of 3 excitation wavelengths under cross-validation using (a) normalization method 1 and (b) normalization method 2.

Tables (1)

Tables Icon

Table 2. Algorithm results for top performing combinations of 1, 2 and 3 excitation wavelengths (λex) using cross validation and both normalization methods.

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