NOMENCLATURE Rubin (1910) introduced the term ‘carcinoma-in-situ’ as a forerunner of invasive carcinoma. Walters and Regan (1956) introduced the concept of dysplasia. Richart (1967) brought-forth the concept of CIN where cervical squamous epithelium is replaced by cells with varying degrees of atypia.
World Health Organization (WHO) in 1975 classified the CIN into three categories correlating with former gradings of dysplasia and CIS. The grading is done according to the thickness occupied by the undifferentiated cells.
Bethesda system (1988) classified cytologic abnormalities of premalignant lesions into three categories:
(a) atypical squamous cells (ASC),
(b) low grade squamous intraepithelial lesions (LSIL) and
(c) high grade squamous intraepithelial lesion (HSIL). LSILs include CIN I and the changes of HPV (Koilocytic atypia).
The cytologic and histologic correlation of mild, moderate and severe dysplasia, carcinoma-in-situ. However, there is considerable degree of overlapping regarding the precise definition of each category of intraepithelial neoplasia. There is no sharp morphologic boundary between them. This creates disagreements in the diagnosis of severity of the lesion.
Thus, the newer terminology CIN, is intended to emphasize that the disease is a continuum and reflects the prognostic significance, if left untreated.
Squamocolumnar junction (SCJ) is the meeting point of columnar epithelium, that lines the endocervical canal, with squamous epithelium that lines the ectocervix. This SCJ is a dynamic point. It moves up and down in relation to different phases of life, e.g. puberty, pregnancy and menopause.
In presence of estrogen the vaginal epithelium accumulates glycogen. The lactobacilli act on glycogen to produce the acid pH (lactic acid) of vagina.
The metaplasia extends from the original SCJ (now squamosquamous) outside to the newly developed (physiologically active) SCJ (now squamocolumnar) inside. This area is defined as transformation zone (TZ).
PATHOGENESIS: The process of carcinogenesis starts at the ‘transformation zone’ (TZ). The zone is not static but in a dynamic state. Two mechanisms are involved in the process of replacement of endocervical columnar epithelium by squamous epithelium.
♦ By squamous metaplasia of the subcolumnar reserve cells.
♦ Squamous epidermidization by ingrowth of the squamous epithelium of the ectocervix under the columnar epithelium.
Initially, the squamous cells are immature but ultimately become mature and indistinguishable to the adjacent squamous epithelium.
This metaplastic process is very active at the time of menarche and during and after first pregnancy.
These periods are of high estrogenic phase which lowers the vaginal pH. The acid pH probably is an important trigger for the metaplastic process. This metaplastic cells have got the potentiality to undergo a typical transformation by trauma or infection.
The prolonged effect of carcinogens can produce continuous changes in the immature cells which may lead to malignancy. Early age sexual activity and multiple sexual partners are the most consistent risk factors. HPV infection is transmitted through sexual activity. Microtrauma (sexual intercourse) causes viral entry to the epithelium (basal or parabasal cells) of the transformation zone adjacent to the SCJ. HPVDNA positivity is strongly related with the number of sexual partners. Women with multiple partners have high HPV DNA positivity rate (60%) compared to women with single partner (21%). The important factors in the genesis of cervical cancer are:
(i) Infection with high-risk HPV,
(ii) Multiple types of HPV,
(iii) Persistence of infection,
(iv) Age > 30 years,
(v) Smoking, and
(vi) Compromised host immunodefense.
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