Large Loop Excision of the Transformation Zone (LLETZ) is thought to be the treatment of choice for the high-grade precancerous lesions. The cone is also the “gold standard” specimen for the diagnosis of the underlying cervical disease once it includes the entire area of carcinogenesis for the squamous epithelium (transformation zone). In most research studies, therapeutic success after conization is a term generally assigned for disease clearance, that is, absence of residual high grade/CIN2+ histology by the end of a reasonable follow-up period, aiming at risk reduction for future recurrence and development of invasion. Conversely, positive cone margins as a reflection of an incomplete excision may, to some extent, represent a negative prognostic factor. Therefore, margin status may also be regarded as an indicator for the quality of a clinical service. The chapter summarizes all current evidence regarding optimal treatment of positive margins after LEEP.
TopThe Importance Of Positive Margins And Individualized Management
In case of positive margins the main question is whether this positivity truly reflects incomplete excision leading to residual disease. This residual disease may be important for two reasons. Firstly, since it is not included in the diagnosed specimen there is always an unknown risk to involve concurrent invasion. Secondly, this possible residual disease may also impose a threat for future development of such an invasion, if left untreated, as it occurs with any primary dysplastic disease.
It is well known from the natural history of HPV related lesions that the majority of the cases represent transient cellular changes that are restored back to normal after an ill-defined period of time ranging from a few months to 3-5 years thus leaving an intact epithelium. Conversely, a minority of the individuals affected by an oncogenic HPV type, will sustain a persistent infection and will follow an oncogenic pathway consisting of cellular transformation leading to carcinogenesis. Although there are no clearly defined causative factors leading to the oncogenic pathway, a number of identifiable parameters are linked statistically with the above disease progress, assisting us to formulate an estimate for the risk of the individual woman to develop invasion and therefore, to offer appropriate management.
Different histologic grades at a given time of diagnosis of the disease reflect different potential for disease progress or regression. A CIN2-3 lesion for example, is more related to persistent infection with E6/E7 expression and stimulation of cell proliferation and a higher risk to advance to neoplasia whereas a Low Grade lesion may merely be the expression of a transient infection with low oncogenic potential and a higher expectation for self-resolution.
Also, the fact that HPV of the lower genital tract is regarded as a common infection, affecting as much as 70 – 80% of the young female population in a typical western society, obviates the existence of “individual factors” or “host factors” for those few ones who will manifest cervical lesions and more so for those, even fewer ones, who will develop invasive disease, among the vast pool of infected subjects. At this point, systemic and local immunity seems to play a pivotal role. Known factors that alter immunity, such as, immunosuppressive diseases, medication, as well as hpv vaccination history are taken into account. Nevertheless, in the majority of cases of High Grade dysplasia there are no such clear, identifiable attributes but other immunity related paremeters have been statistically associated with pre-cancerous lesions, namely smoking, dietary habits and lifestyle related to sexual behavior.
The type of hr-HPV also plays a significant role in the disease progress. HPV 16 for example, has an average length of persistence that is longer than most other high-risk types, and this may contribute to its higher cancer risk. This applies to a lesser extend, to other hr-hpv types. Other types (like type 18) seem to express a higher tropism for lesions extending to the glandular epithelium; therefore the type of hpv involved in a residual lesion is valuable information.