Abstract

Acetic acid, inducing transient whitening (acetowhitening) when applied to epithelial tissues, is a commonly used contrast agent for detecting early cervical cancer. The goals of this research are to investigate the temporal characteristics of acetowhitening process in cervical epithelial tissue at cellular level and develop a clear understanding of the diagnostic information carried in the acetowhitening signal. A system measuring time-resolved reflectance was built to study the rising and decay processes of acetowhitening signal from the monolayered cell cultures of normal and cancerous cervical squamous cells. It is found that the dynamic processes of acetowhitening in normal and cancerous cells are significantly different. The results of this study provide insight valuable to further understand the acetowhitening process in epithelial cells and to encourage the development of an objective procedure to detect the early cervical cancers based on quantitative monitoring of the dynamic process of acetowhitening.

©2005 Optical Society of America

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References

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  1. T. C. Wright, R. J. Kurman, and A. Ferenczy, “Cervical Intraepithelial Neoplasia,” in Blaustein A. Pathology of the Female Genital Tract (Springer-Verlag, New York, 1994).
  2. U.S. Preventive Services Task Force, Guide to clinical preventive services: report of the U.S. Preventive Services Task Force (Williams & Wilkins, 1996).
  3. M. C. Anderson, J. A. Jordan, A. R. Morse, and F. Sharp, A Text and Atlas of Integrated Colposcopy: for Colposcopists, Histopathologists and Cytologists (Chapman & Hall Medical, 1992).
  4. M. F. Mitchell, “The Accuracy of Colposcopy,” Clinical Consultations in Obstetrics and Gynecology 6, 70–73, (1994).
  5. M. Ronne, “Chromosome preparation and high resolution banding techniques. A review,” J. Dairy Sci. 72, 1363–1377, (1989).
    [Crossref] [PubMed]
  6. S. Yamada, D. Wirtz, and P. A. Coulombe, “Pairwise Assembly Determines the Intrinsic Potential for Self-Organization and Mechanical Properties of Keratin Filaments,” Mol. Biol. Cell 13, 382–391, (2002).
    [Crossref] [PubMed]
  7. R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and Chromoscopy with the Acetic Acid Test,” Endoscopy 35, 437–445, (2003).
    [Crossref] [PubMed]
  8. C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
    [Crossref]
  9. B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
    [Crossref] [PubMed]
  10. C. Balas, “A Novel Optical Imaging Method for the Early Detection, Quantitative Grading, and Mapping of Cancerous and Precancerous Lesions of Cervix,” IEEE Trans. Biomed. Eng. 48, 96–104, (2001).
    [Crossref] [PubMed]
  11. R. S. Cotran, V. Kumar, and T. Collins, Robbins Pathologic Basis of Disease (W. B. Saunders, 1999).
  12. M. A. Stanley, “Culture of Human Cervical Epithelial Cells”, in Culture of Epithelial Cells, R. I. Freshney and M. G. Freshney, eds. (Wiley-Liss, 2002).

2003 (1)

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and Chromoscopy with the Acetic Acid Test,” Endoscopy 35, 437–445, (2003).
[Crossref] [PubMed]

2002 (1)

S. Yamada, D. Wirtz, and P. A. Coulombe, “Pairwise Assembly Determines the Intrinsic Potential for Self-Organization and Mechanical Properties of Keratin Filaments,” Mol. Biol. Cell 13, 382–391, (2002).
[Crossref] [PubMed]

2001 (2)

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

C. Balas, “A Novel Optical Imaging Method for the Early Detection, Quantitative Grading, and Mapping of Cancerous and Precancerous Lesions of Cervix,” IEEE Trans. Biomed. Eng. 48, 96–104, (2001).
[Crossref] [PubMed]

1998 (1)

C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
[Crossref]

1994 (1)

M. F. Mitchell, “The Accuracy of Colposcopy,” Clinical Consultations in Obstetrics and Gynecology 6, 70–73, (1994).

1989 (1)

M. Ronne, “Chromosome preparation and high resolution banding techniques. A review,” J. Dairy Sci. 72, 1363–1377, (1989).
[Crossref] [PubMed]

Anderson, M. C.

M. C. Anderson, J. A. Jordan, A. R. Morse, and F. Sharp, A Text and Atlas of Integrated Colposcopy: for Colposcopists, Histopathologists and Cytologists (Chapman & Hall Medical, 1992).

Balas, C.

C. Balas, “A Novel Optical Imaging Method for the Early Detection, Quantitative Grading, and Mapping of Cancerous and Precancerous Lesions of Cervix,” IEEE Trans. Biomed. Eng. 48, 96–104, (2001).
[Crossref] [PubMed]

Burke, E. E.

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

Burke, G. C.

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

Collier, T.

C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
[Crossref]

Collins, T.

R. S. Cotran, V. Kumar, and T. Collins, Robbins Pathologic Basis of Disease (W. B. Saunders, 1999).

Cotran, R. S.

R. S. Cotran, V. Kumar, and T. Collins, Robbins Pathologic Basis of Disease (W. B. Saunders, 1999).

Coulombe, P. A.

S. Yamada, D. Wirtz, and P. A. Coulombe, “Pairwise Assembly Determines the Intrinsic Potential for Self-Organization and Mechanical Properties of Keratin Filaments,” Mol. Biol. Cell 13, 382–391, (2002).
[Crossref] [PubMed]

Drezek, R.

C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
[Crossref]

Dunn, A.

C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
[Crossref]

Ferenczy, A.

T. C. Wright, R. J. Kurman, and A. Ferenczy, “Cervical Intraepithelial Neoplasia,” in Blaustein A. Pathology of the Female Genital Tract (Springer-Verlag, New York, 1994).

Harper, D. M.

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

Harper, W.

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

Jordan, J. A.

M. C. Anderson, J. A. Jordan, A. R. Morse, and F. Sharp, A Text and Atlas of Integrated Colposcopy: for Colposcopists, Histopathologists and Cytologists (Chapman & Hall Medical, 1992).

Kaufman, H. B.

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

Kumar, V.

R. S. Cotran, V. Kumar, and T. Collins, Robbins Pathologic Basis of Disease (W. B. Saunders, 1999).

Kurman, R. J.

T. C. Wright, R. J. Kurman, and A. Ferenczy, “Cervical Intraepithelial Neoplasia,” in Blaustein A. Pathology of the Female Genital Tract (Springer-Verlag, New York, 1994).

Lambert, R.

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and Chromoscopy with the Acetic Acid Test,” Endoscopy 35, 437–445, (2003).
[Crossref] [PubMed]

Mitchell, M. F.

M. F. Mitchell, “The Accuracy of Colposcopy,” Clinical Consultations in Obstetrics and Gynecology 6, 70–73, (1994).

Morse, A. R.

M. C. Anderson, J. A. Jordan, A. R. Morse, and F. Sharp, A Text and Atlas of Integrated Colposcopy: for Colposcopists, Histopathologists and Cytologists (Chapman & Hall Medical, 1992).

Pogue, B. W.

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

Rey, J. F.

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and Chromoscopy with the Acetic Acid Test,” Endoscopy 35, 437–445, (2003).
[Crossref] [PubMed]

Richards-Kortum, R.

C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
[Crossref]

Ronne, M.

M. Ronne, “Chromosome preparation and high resolution banding techniques. A review,” J. Dairy Sci. 72, 1363–1377, (1989).
[Crossref] [PubMed]

Sankaranarayanan, R.

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and Chromoscopy with the Acetic Acid Test,” Endoscopy 35, 437–445, (2003).
[Crossref] [PubMed]

Sharp, F.

M. C. Anderson, J. A. Jordan, A. R. Morse, and F. Sharp, A Text and Atlas of Integrated Colposcopy: for Colposcopists, Histopathologists and Cytologists (Chapman & Hall Medical, 1992).

Smithpeter, C.

C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
[Crossref]

Stanley, M. A.

M. A. Stanley, “Culture of Human Cervical Epithelial Cells”, in Culture of Epithelial Cells, R. I. Freshney and M. G. Freshney, eds. (Wiley-Liss, 2002).

Wirtz, D.

S. Yamada, D. Wirtz, and P. A. Coulombe, “Pairwise Assembly Determines the Intrinsic Potential for Self-Organization and Mechanical Properties of Keratin Filaments,” Mol. Biol. Cell 13, 382–391, (2002).
[Crossref] [PubMed]

Wright, T. C.

T. C. Wright, R. J. Kurman, and A. Ferenczy, “Cervical Intraepithelial Neoplasia,” in Blaustein A. Pathology of the Female Genital Tract (Springer-Verlag, New York, 1994).

Yamada, S.

S. Yamada, D. Wirtz, and P. A. Coulombe, “Pairwise Assembly Determines the Intrinsic Potential for Self-Organization and Mechanical Properties of Keratin Filaments,” Mol. Biol. Cell 13, 382–391, (2002).
[Crossref] [PubMed]

Zelenchuk, A.

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

Clinical Consultations in Obstetrics and Gynecology (1)

M. F. Mitchell, “The Accuracy of Colposcopy,” Clinical Consultations in Obstetrics and Gynecology 6, 70–73, (1994).

Endoscopy (1)

R. Lambert, J. F. Rey, and R. Sankaranarayanan, “Magnification and Chromoscopy with the Acetic Acid Test,” Endoscopy 35, 437–445, (2003).
[Crossref] [PubMed]

IEEE Trans. Biomed. Eng. (1)

C. Balas, “A Novel Optical Imaging Method for the Early Detection, Quantitative Grading, and Mapping of Cancerous and Precancerous Lesions of Cervix,” IEEE Trans. Biomed. Eng. 48, 96–104, (2001).
[Crossref] [PubMed]

J. Biomed. Opt. (2)

C. Smithpeter, A. Dunn, R. Drezek, T. Collier, and R. Richards-Kortum, “Near Real Time Confocal Microscopy of Cultured Amelanotic Cells: Sources of Signal, Contrast Agents, and Limits of Contrast,” J. Biomed. Opt. 3, 429–436 (1998).
[Crossref]

B. W. Pogue, H. B. Kaufman, A. Zelenchuk, W. Harper, G. C. Burke, E. E. Burke, and D. M. Harper, “Analysis of Acetic Acid-Induced Whitening of High-Grade Squamous Intraepithelial Lesions,” J. Biomed. Opt. 6, 397–403, (2001).
[Crossref] [PubMed]

J. Dairy Sci. (1)

M. Ronne, “Chromosome preparation and high resolution banding techniques. A review,” J. Dairy Sci. 72, 1363–1377, (1989).
[Crossref] [PubMed]

Mol. Biol. Cell (1)

S. Yamada, D. Wirtz, and P. A. Coulombe, “Pairwise Assembly Determines the Intrinsic Potential for Self-Organization and Mechanical Properties of Keratin Filaments,” Mol. Biol. Cell 13, 382–391, (2002).
[Crossref] [PubMed]

Other (5)

T. C. Wright, R. J. Kurman, and A. Ferenczy, “Cervical Intraepithelial Neoplasia,” in Blaustein A. Pathology of the Female Genital Tract (Springer-Verlag, New York, 1994).

U.S. Preventive Services Task Force, Guide to clinical preventive services: report of the U.S. Preventive Services Task Force (Williams & Wilkins, 1996).

M. C. Anderson, J. A. Jordan, A. R. Morse, and F. Sharp, A Text and Atlas of Integrated Colposcopy: for Colposcopists, Histopathologists and Cytologists (Chapman & Hall Medical, 1992).

R. S. Cotran, V. Kumar, and T. Collins, Robbins Pathologic Basis of Disease (W. B. Saunders, 1999).

M. A. Stanley, “Culture of Human Cervical Epithelial Cells”, in Culture of Epithelial Cells, R. I. Freshney and M. G. Freshney, eds. (Wiley-Liss, 2002).

Supplementary Material (3)

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» Media 3: MOV (203 KB)     

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Figures (8)

Fig. 1.
Fig. 1. Schematic of time-resolved reflectance measurement system. L1: Focus Lens (f=35mm); C1: Fiber Optic Collimator; A1: Aperture Stop; M1, M2: Mirrors.

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Fig. 2.
Fig. 2. Acetowhitening signals (right) and phase-contrast images (left) recorded from cancer cell samples in rising and decay courses. (a) (1.228MB) Concentration of acetic acid in medium: 0.3%; (b) (962KB) Concentration of acetic acid in medium: 1.2%.

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Fig. 3.
Fig. 3. Wavelength-dependence of acetowhitening signal. (a) RGB reflectance signals recorded from a cancer cell sample with the application of 0.6% acetic acid solution; (b) Comparison of RGB signals in the rising course; (c) Comparison of signals in the decay course.

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Fig. 4.
Fig. 4. Acetowhitening signals of cancer cell samples at different acetic acid concentrations. (a) (203KB) Movie of the acetowhitening signals as a function of acetic acid concentration; (b) The peak value of acetowhitening signals as a function of acetic acid concentration.

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Fig. 5.
Fig. 5. Comparison of the acetowhitening signals of cancer cell samples when applying the medium with different acetic acid concentrations. (a) Normalized signals in the rising courses; (b) Normalized signals in the decay courses.

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Fig. 6.
Fig. 6. Acetowhitening signals of normal cell samples at different acetic acid concentrations. (a) The acetowhitening signals as a function of acetic acid concentration; (b) The peak value of acetowhitening signals as a function of acetic acid concentration.

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Fig. 7.
Fig. 7. Comparison of single and dual-exponential models in fitting the decay of acetowhitening signals. (a) Cancer cell sample, 0.6% acetic acid; (b) Normal cell sample, 0.6% acetic acid.

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Fig. 8.
Fig. 8. (a) pH value and (b) H+ concentration (mol/L) of the acetic acid solution as a function of the concentration of acetic acid at room temperature 25°C.

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Tables (2)

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Table 1. The decay time constants for normal and cancer cell samples calculated from a single exponential model.

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Table 2. Analyses of decay process of acetowhitening effect in normal and cancer cells using dual-exponential model.

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