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 PRACTICE RECOMMENDATIONS: Practice Management Materials • Vulva • Vagina • Cervix • Anus |
THE CERVIX: Histology of the Normal Cervix An understanding of the histology of the cervix is critical to the use of effective cytologic screening, colposcopy, and biopsy results in the management and treatment of cervical neoplasia. The stroma of the cervix, which accounts for most of its mass and shape, is composed of dense, fibromuscular tissue made up of collagenous connective tissue (smooth muscle and elastic tissue) and ground substance (mucopolysaccharide). Through the stroma course the vascular, lymphatic, and nervous supplies of the cervix. While of great importance to the structure and obstetrical functioning of the cervix, the stroma plays little role in cervical neoplasia. Rather, it is the epithelium of the cervix which gives rise to cervical neoplasia. Therefore, this section will focus on the cervical epithelium. The cervix is covered by both columnar and stratified non-keratinising squamous epithelia. The squamocolumnar junction, where these two meet, is the most important cytologic and colposcopic landmark, as this is where over 90% of lower genital tract neoplasia arises. This junction is presumed, but not proven, to be the embryologic junction of the Müllerian and urogenital sinus epithelia. SQUAMOUS EPITHELIUM The squamous epithelium of the cervical portio is similar to that of the vagina, except that it is generally smooth and lacks rete pegs. Colposcopically, it appears featureless except for a fine network of vessels which is sometimes visible. The relative opacity and pale pink coloration of the squamous epithelium derives from its multi-layered histology and the location of its supporting vessels below the basement membrane. A full description of the histology and maturation of squamous epithelium can be found in any number of pathology texts and will not be detailed here. Mature squamous epithelium (H&E x 400): Different layers starting at the basement membrane (basal, parabasal, intermediate, superficial) are evident. Clear cytoplasm indicates glycogenation. As the cells mature, the nuclei get smaller and the cytoplasm amount increases. The maturation and glycogenation of the squamous epithelia of the vagina and cervix are influenced by ovarian hormones. Estradiol promotes maturation, glycogenation, and desquamation. Progesterone inhibits superficial maturation. This explains why the squamous epithelium appears atrophic after loss of ovarian function, with pallor and subepithelial point-hemorrhages from increased vulnerability of the underlying vessels. These atrophic changes may be seen, albeit less dramatically, with prolonged exposure to progestins, as with injectable progestin-only contraceptives. Glycogenation of the mature squamous epithelium of the vagina and cervix under the influence of estrogen give rise to the strong uptake of Lugol’s iodine solution. This is the basis of Schiller’s test, used to help distinguish normal tissue from abnormal. Dysplastic or HPV-infected squamous epithelium show arrested maturation with incomplete or absent glycogenation and will reject iodine staining. It may also show abnormal deposition of keratin in the upper layers of the epithelium. Parakeratosis (H&E x 400): Orange layer of keratin above the superficial squamous epithelial cells. The blue cell layer beneath the keratin indicates the production of keratin granules. Nuclei in the keratin is parakeratosis. GLANDULAR EPITHELIUM The “glandular” or columnar epithelium of the cervix is located cephalad to the squamo-columnar junction. It covers a variable amount of the ectocervix and lines the endocervical canal. It is comprised of a single layer of mucin-secreting cells. The epithelium is thrown into longitudinal folds and invaginations that make up the so-called endocervical glands (they are not true glands). These infolding crypts and channels make the cytologic and colposcopic detection of neoplasia less reliable and more problematic. The complex architecture of the endocervical glands gives the columnar epithelium a papillary appearance through the colposcope and a grainy appearance upon gross visual inspection. The single cell layer allows the coloration of the underlying vasculature to be seen more easily. Therefore, the columnar epithelium is appears redder in comparison with the more opaque squamous epithelium. ECC: (H&E x 40): Mucus and small unoriented fragments of endocervical glands Endocervical glands (H&E x 400): Actually crypts (there are no acini and ducts) lined by a single layer of columnar epithelium. Extend to a depth of 5-7 mm. Nl endocervix (H&E x 400): Single layer of columnar cells with basal nuclei. MUCOSAL IMMUNITY Both the secretory (IgA mediated) and cellular immune systems are active within the cervical epithelia and stroma. In particular, macrophages, including some Langerhans cells, -lymphocytes are present. Local immunity is suspected to play an important role in the wide variety of outcomes seen among individuals following HPV infection and in the susceptibility to the development of neoplasia. Squamocolumnar Junction The squamocolumnar junction (SCJ) is defined as the junction between the squamous epithelium and the glandular epithelium. It is often marked by a line of metaplasia and its location is variable. Age and hormonal status are the most important factors influencing its location. During the perimenarche, the SCJ is located at or very close to the external os. The SCJ is generally located on the ectocervix at variable distances from the os in reproductive-aged women, as the cervix, and particularly the endocervical canal elongates under the influence of estrogen. The high estrogen levels of pregnancy and oral contraceptive use promote further eversion of the SCJ. Eversion is usually more pronounced on the anterior and posterior lips of the ectocervix and less so at the 3 and 9 o'clock positions. Eversion of the columnar epithelium onto the ectocervix may not be symmetrical. The resulting asymmetric appearance may cause confusion and prompt a referral for a possible cervical lesion. An eversion of the SCJ onto the ectocervix is sometimes referred to as an “ectropion “ or “erosion.” The latter term is a misnomer and should not be used. Occasionally, the SCJ is located in part or entirely on the vaginal fornices. The process of squamous epithelialization of the vaginal tube begins at the dorsal urogenital sinus and vaginal plate, spreading upwards along the vaginal tube. This process proceeds most rapidly along the lateral walls. If the epithelialization proceeds normally, the SCJ is located at near the external os of the cervix. If the epithelialization is arrested before completion, the SCJ will be located on the vaginal walls, usually involving the anterior and posterior vaginal fornices, as epithelialization in these locations occurs later than laterally. This type of variant in SCJ location are most striking in in-utero DES-exposed women. In some cases the entire cervical portio will be covered with columnar epithelium. From the perimenopause on, or with prolonged exposure to strong progestational agents which cause atrophy, the SCJ recedes up the endocervical canal. This makes cytologic sampling less reliable and colposcopic examination of the SCJ impossible in many cases. Squamocolumnar junction (H&E x 400): Junction of single layer columnar cells and stratified squamous cells. Identifying the location of the SCJ is important for the optimal collection of cytologic samples. Therefore, the acquisition of cells should be modified from patient to patient to insure that the area at risk for neoplasia is targeted. The location of the SCJ also determines in large part the efficacy of colposcopy in ruling out the presence of neoplasia. If the SCJ cannot be visualized in its entirety, the colposcopy is deemed “unsatisfactory.” Finally, the location of the SCJ influences the choice of treatment modality if neoplasia is present. TRANSFORMATION ZONE An understanding of the cervical transformation zone (TZ) is essential to the identification and management of cervical intraepithelial neoplasia. It lies between the “original” and “new” squamocolumnar junctions. The SCJ discussed above is the visible border between the squamous and columnar epithelia of the cervix and represents the new squamocolumnar junction. It is adjacent to the new SCJ that the dynamic process of squamous metaplasia occurs throughout the reproductive years. This is a normal process during which columnar epithelium is replaced by squamous. The trigger for this process is thought to be the eversion of the columnar epithelium under the influence of estrogen and its subsequent exposure to the acidic vaginal pH. In response to the “insult” of vaginal acidity, the process of metaplasia replaces the more fragile columnar epithelium with the more sturdy squamous type. This process is thought to occur by two mechanisms. One is by reserve cell hyperplasia. Reserve cells proliferate around the exposed endocervical glands and eventually obliterate and replace them. The columnar epithelium is replaced, not changed into another type of epithelium. Reserve cells (H&E x 400): single layer of round undifferentiated cells beneath the columnar cells. Colposcopically, this process is seen as a flattening out and merging of the villous structures of the glandular tissue, with replacement by a smoother, milky coating. It is also thought that some metaplasia occurs by the ingrowth of squamous epithelium centripetally from the squamous epithelium of the ectocervix. This ingrowth undermines and replaces the overlying columnar epithelium. The net result is a zone of squamous metaplasia of variable width distal (caudal) to the columnar epithelium and proximal (cephalad) to the “original squamous epithelium” laid down during embyogenesis. Immature squamous metaplasia (H&E x 400): Proliferation of reserve cells results in a 3-5 cell layer of nonglycogenated metaplastic cells. The remnant columnar cells are at the surface. The border between the metaplastic epithelium arising during the reproductive years and the original squamous epithelium is called the “original SCJ.” The TZ is the area of metaplastic epithelium between the original and new SCJs. During the process of metaplasia, still-functioning endocervical glands may become covered and blocked, giving rise to Nabothian cysts. Cervix Biopsy (H&E x 25): Squamous epithelium overlying glands indicates the presence of the transformation zone. The metaplastic epithelium adjacent to the new SCJ is the newest and the least mature squamous epithelium on the cervix. As new metaplastic epithelium arises, the older metaplastic epithelium is moved outward toward the original SCJ, with the newest and least mature metaplasia adjacent to the new SCJ. With time, the metaplastic epithelium matures to the point where its thickness and glycogenation is indistinguishable from the original squamous epithelium. This makes the colposcopic identification of the original SCJ, and therefore the outer limits of the TZ, impossible in many cases. The location of Nabothian cysts, always formed within the TZ, is useful in identifying its limits. The identification of the TZ is of utmost importance to the colposcopist. It is within the metaplastic epithelium, i.e. the TZ, that essentially all cervical neoplasia arises. Metaplasia is particularly active during the peripubertal years and during the first pregnancy. Perhaps this accounts for the fact that early first sexual intercourse and early age at first pregnancy are risk factors for cervical cancer. It is hypothesized that the reserve cells in adolescent and young women are especially vulnerable to the oncogenic potential of human papillomavirus infection. The size and location of the TZ will influence selection of treat modality if neoplasia is present. COLPOSCOPIC AND NEOPLASTIC SIGNIFICANCE OF THE TRANSFORMATION ZONE Nearly all cervical neoplasia occurs in the TZ. This is even true of the adenocarcinomas, which are often associated with adjacent high-grade squamous disease, although they may rarely occur higher up in the endocervical canal. This is because it is the reserve cells undergoing metaplasia that are vulnerable to various carcinogens such as HPV. Since metaplasia is at peak activity during adolescence and first pregnancy, it is understandable that early age on sexual activity and first pregnancy are known risk factors for cervical cancer. It is therefore of great importance that the colposcopist be able to identify and evaluate the TZ. Given a particular lesion, the more severe disease tends to be cephalad in the TZ, where the epithelium is least mature. In order that a colposcopic exam may be deemed “satisfactory” or “adequate,” the TZ must be seen in its entirety, all the way up to the columnar epithelium, 360°, which means that all areas involved in squamous metaplasia have been visualized. If this is not possible, because the new SCJ or abnormalities are up inside the canal beyond view, then one cannot be sure that a high-grade lesion or cancer has been ruled out The importance of the TZ to cervical neoplasia explains why it is desirable to see both columnar (endocervical) and squamous metaplastic cells on Pap smears. Their presence indicates that the area at risk has indeed been sampled. HISTOLOGY AND COLPOSCOPY OF THE TRANSFORMATION ZONE As reserve cell hyperplasia progresses to several layers of thickness, the columnar epithelium is pushed off and replaced. This proliferation of reserve cells is seen as the flattening and fusing of columnar villi. The areas of metaplasia are paler than the one-cell-thick columnar epithelium as the underlying blood vessels are now viewed through several cell layers. Metaplasia is usually seen as numerous small. glassy islands overlying the columnar epithelium and also as pale, translucent ingrowths of metaplasia from the original squamous epithelium. These islands and tongues of metaplasia can be irregularly shaped and distributed around the TZ, and coalesce into sheets of metaplasia, often with a thin acetowhite line at the advancing border. Immature metaplasia can turn acetowhite, causing striking “frosting” of these areas. As the epithelium matures and pushes “outward” relative to the external os of the cervix, it shows a gradient of maturity. The maturest epithelium is densest with at most a trivial, fine vascular pattern. It does not turn acetowhite. It also has the highest level of glycogenation and therefore iodine uptake. Less mature metaplasia may be a pale acetowhite and may show fine vascular patterns that are can both be confused with low-grade lesions. When the crypts of the mucin-secreting columnar epithelium become covered up by metaplastic epithelium, they become blocked, and Nabothian cysts are formed. Therefore, these cysts are by definition located within the TZ. The vessel overlying Nabothian cysts can be large and alarming to the novice colposcopist. However, close inspection will reveal their benign, arborizing character. The most mature metaplastic epithelium probably has little neoplastic potential, like that of the original squamous epithelium. Some women have a large area of acetowhite, iodine-variable epithelium which extends onto the anterior and / or posterior vaginal fornices. There may also be a very fine mosaic pattern. This is called a congenital TZ and is caused by squamous epithelium of arrested maturation and variable glycogenation, probably laid down during fetal development. This epithelium is of low neoplastic potential and can be very confusing to the colposcopist. PREGNANCY-RELATED CHANGES The cervix in pregnancy shows stromal edema, increased vascularity, enlargement of glandular structures, and acute inflammatory response. Stromaldecidualization may occur in the second and third trimesters; these changes may appear suspicious to the inexperienced observer. REFERENCES Systemic Pathology / Third Edition, Vol. 6, Female Reproductive System. Ed. MC Anderson. Churchill Livingston, London, 1991 Blaustein’s Pathology of the Female Genital Tract / Fourth Edition. Ed. RJ Kurman. Springer-Verlag, New York, 1994  |
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