Transferring knowledge and techniques that have been learned from decades of the use of acetic acid in colposcopy to the field of digestive endoscopy is a noteworthy objective. However, to be accurate, the fundamental mechanism involved in the whitening of cervical tissue after the application of acetic acid - the process known as ”acetowhitening” - has not yet been definitively clarified. In a recent paper in Endoscopy, Lambert et al. claim that ”Cytokeratins are the major cause of the acetowhite reaction, due to their filamentous architecture” [ 1 ]. This hypothesis does not explain other acetowhitening phenomena observed in nonneoplastic tissue. For example, crypt openings (resulting in so-called ”cuffed gland openings”), borders of the transformation zone, and immature metaplasia can all display whitening characteristics similar to the whitening observed with tissue classified as cervical intraepithelial neoplasia (CIN) grades I, II, and III. In fact, since nonneoplastic tissue can acetowhiten and mimic neoplastic tissue, there is a need for improved diagnostic training and/or new techniques to improve the accuracy of classifying whitened tissue when observed colposcopically. An alternative explanation for the fundamental mechanism of the acetowhitening phenomenon is based on another concept mentioned by Lambert et al. The phenomenon of the wrapping and unwrapping of DNA around the core histones in the nucleus is often referred to as ”chromatin condensation.” Chromatin condensation and decondensation - the reversal of the process several minutes after the application of acetic acid - can be used to explain the primary mechanism of acetowhitening. Chromatin condensation occurs when the macrostructural properties of tissue allow for the permeation of acetic acid through the epithelial cell membranes to the cell nuclei. When acetic acid is introduced into highly permeable epithelial tissue, such as neoplastic tissue and certain categories of nonneoplastic tissue, the tissue whitens as a function of the nuclei/chromatin density. The intensity and rate of the acetowhitening phenomenon are proportionate to the density of the nuclei and the permeability of the tissue to acetic acid. When densely packed nuclei are accessible to acetic acid, an observable acetowhitening effect will occur. When epithelial cells are intact, highly differentiated, and acting as an effective barrier to acetic acid, little or no acetowhitening is observable. The following is a discussion supporting this macrostructurally based explanation as the key mechanism involved in the acetowhitening of both neoplastic and nonneoplastic cervical tissue. Previously published work has discussed the acetowhitening phenomenon in cervical tissue. Drezek et al. hypothesized that the predominant effect involved in acetowhitening is ”an alteration of the refractive-index structure of the [cell’s] nucleus” [ 2 ]. Rajadhyaksha et al. hypothesized that, in addition to changes in the back-scattering properties of cells, acetic acid may also increase depolarization from intranuclear structures [ 3 ]. Both groups explain the acetowhitening phenomenon in terms of intracellular changes or relatively microstructural phenomena. The alternative, which may complement or possibly even dominate the cellular mechanism of acetowhitening, is a macrostructural intercellular mechanism. It is well known that high-grade intraepithelial neoplasia results in a very brittle surface tissue structure. Within high-grade lesions, ”epithelial edges tend to detach from underlying stroma and curl back on themselves” [ 4 ]. This lends itself well to cell exfoliation of diseased cells, which are readily detectable in Papanicolaou smears. It also implies that intercellular cohesiveness may play an important role in the progression of neoplastic disease. For acetic acid to penetrate cells and change the intracellular optical properties, there must be an effective surface area of cells that are exposed to the acetic acid. In normal squamous epithelial cervical tissue, the several uppermost layers of cells are highly differentiated and form a relatively impenetrable barrier against the penetration of liquids. However, other conditions exist that can increase the surface area of cells exposed to acetic acid. These include crypt openings (resulting in ”cuffed gland openings”); the borders of the transformation zone; immature metaplasia; and compromised cell junctions. Crypt openings (resulting in ”cuffed gland openings”). Gland or crypt openings on the surface of the cervix will often whiten in a characteristic ”cuffed” pattern (Figure [ 1 ]) [ 5 ]. A Japanese group [ 6 ] went as far as to claim that the colposcopic diagnosis of cervical neoplasia could be aided by the identification of certain patterns of whitening around gland openings. Nevertheless, gland openings provide a channel or conduit for acetic acid to pass the top highly differentiated squamous-cell level and result in the increased surface area of glandular or columnar cells exposed to acetic acid. Figure 1 An example of ”cuffed” glands in nondiseased tissue, produced by acetowhitening. From Anderson et al., Integrated colposcopy (Philadelphia, 1997) [ 5 ], reproduced with permission from Lippincott Williams & Wilkins. Borders of the transformation zone. As with crypt or gland openings, the tissue morphology around the transformation zone often results in a cliff-like step between the high normal squamous epithelium and the lower columnar or metaplastic tissue (Figure [ 2 ]). This step provides en-face exposure - the ”side of the cliff,” as it were - to acetic acid. The cells on this cliff face therefore have a larger surface area exposed to the acetic...