The physiological replacement of the everted columnar epithelium by a newly formed squamous epithelium is called squamous metaplasia. The vaginal environment is acidic during the reproductive years and during pregnancy. The acidity is thought to play a role in squamous metaplasia. When the cells are repeatedly destroyed by vaginal acidity in the columnar epithelium in an area of ectropion, they are eventually replaced by a newly formed metaplastic epithelium. The irritation of exposed columnar epithelium by the acidic vaginal environment results in the appearance of sub-columnar reserve cells. These cells proliferate producing a reserve cell hyperplasia and eventually form the metaplastic squamous epithelium.
As already indicated, the metaplastic process requires the appearance of undifferentiated, cuboidal, sub-columnar cells called reserve cells (Figure 1.9a
), for the metaplastic squamous epithelium is produced from the multiplication and differentiation of these cells. These eventually lift off the persistent columnar epithelium (Figures 1.9b and 1.9c
). The exact origin of the reserve cells is not known, though it is widely believed that it develops from the columnar epithelium, in response to irritation by the vaginal acidity.
The first sign of squamous metaplasia is the appearance and proliferation of reserve cells (Figures 1.9a and 1.9b
). This is initially seen as a single layer of small, round cells with darkly staining nuclei, situated very close to the nuclei of columnar cells, which further proliferate to produce a reserve cell hyperplasia (Figure 1.9b
). Morphologically, the reserve cells have a similar appearance to the basal cells of the original squamous epithelium, with round nuclei and little cytoplasm. As the metaplastic process progresses, the reserve cells proliferate and differentiate to form a thin, multicellular epithelium of immature squamous cells with no evidence of stratification (Figure 1.9c
). The term immature squamous metaplastic epithelium is applied when there is little or no stratification in this thin newly formed metaplastic epithelium. The cells in the immature squamous metaplastic epithelium do not produce glycogen and, hence, do not stain brown or black with Lugol’s iodine solution. Groups of mucin-containing columnar cells may be seen embedded in the immature squamous metaplastic epithelium at this stage.
Numerous continuous and/or isolated fields or foci of immature squamous metaplasia may arise at the same time. It has been proposed that the basement membrane of the original columnar epithelium dissolves and is reformed between the proliferating and differentiating reserve cells and the cervical stroma. Squamous metaplasia usually begins at the original squamocolumnar junction at the distal limit of the ectopy, but it may also occur in the columnar epithelium close to this junction or as islands scattered in the exposed columnar epithelium.
As the process continues, the immature metaplastic squamous cells differentiate into mature stratified metaplastic epithelium (Figure 1.9d
). For all practical purposes, the latter resembles the original stratified squamous epithelium. Some residual columnar cells or vacuoles of mucus are seen in the mature squamous metaplastic epithelium, which contains glycogen from the intermediate cell layer onwards. Thus, it stains brown or black after application of Lugol’s iodine. Several cysts, called nabothian cysts (follicles), may be observed in the mature metaplastic squamous epithelium (1.10
). Nabothian cysts are retention cysts that develop as a result of the occlusion of an endocervical crypt opening or outlet by the overlying metaplastic squamous epithelium (1.10
). The buried columnar epithelium continues to secrete mucus, which eventually fills and distends the cyst. The entrapped mucus gives an ivory-white to yellowish hue to the cyst on visual examination (1.11
). The columnar epithelium in the wall of the cyst is flattened and ultimately destroyed by the pressure of the mucus in it. The outlets of the crypts of columnar epithelium, not yet covered by the metaplastic epithelium, remain as persistent crypt openings. The farthest extent of the metaplastic epithelium onto the ectocervix can be best judged by the location of the crypt opening farthest away from the squamocolumnar junction.
Squamous metaplasia is an irreversible process; the transformed epithelium (now squamous in character) cannot revert to columnar epithelium. The metaplastic process in the cervix is sometimes referred to as indirect metaplasia, as the columnar cells do not transform into squamous cells, but are replaced by the proliferating sub-columnar cuboidal reserve cells. Squamous metaplasia may progress at varying rates in different areas of the same cervix, and hence many areas of widely differing maturity may be seen in the metaplastic squamous epithelium with or without islands of columnar epithelium. The metaplastic epithelium adjacent to the squamocolumnar junction is composed of immature metaplasia, and the mature metaplastic epithelium is found near the original squamocolumnar junction.
Further development of the newly formed immature metaplastic epithelium may take two directions (1.12
). In the vast majority of women, it develops into a mature squamous metaplastic epithelium, which is similar to the normal glycogen-containing original squamous epithelium for all practical purposes. In a very small minority of women, an atypical, dysplastic epithelium may develop. Certain oncogenic human papillomavirus (HPV) types may persistently infect the immature basal squamous metaplastic cells and transform them into atypical cells with nuclear and cytoplasmic abnormalities. The uncontrolled proliferation and expansion of these atypical cells may lead to the formation of an abnormal dysplastic epithelium which may regress to normal, persist as dysplasia or progress into invasive cancer after several years.
It is also thought that some metaplasia may occur by in-growth of the squamous epithelium from the squamous epithelium of the ectocervix.