Factors predictors of residual illness in patient conizadas for lesions micro invaders and of high degree

In Cuba, the cervical cancer constitutes an important problem of health for its high indexes of morbi-mortality and emotional impact in the population. In the handling of the women with their lesions precursors, the objective consists on preventing the possible progression to cancer invader without sobretratar the lesions with high regression probabilities. Along the time different treatments and protocols have been proven in order to obtaining the best results in the control of this pathology with conservative techniques, in the face of the growing incidence in patient without satisfied parity and minimizing the possibility of residual illness. It was carried out a prospective descriptive study to determine the relationship between the diagnosis of residual illness and clinical-epidemic factors in 428 patients with lesions cervical epithelial of high degree that were conization in the Hospital General Educational Heroes of the Baire during the period 2014-2016. 53% of the studied patients was bigger than 35 years of age, 74% had one or two children, 20% smoked, 38% had an initial cytology of high degree, 46% they had a lesion with an area of 100-199mm2, 90% they were conization for handle diathermic and 29% they were conization for not correlation diagnostics. The surgical margins affected by lesion, the carcinoma histology in situ or micro invader, the area of more lesion 199mm2 and the glandular lesions of the cervical channel constituted factors predictors of residual illness. The presence of these factors predictors meant 79,6% of probability of appearance of residual lesion. Correspondence to: Heenry Luis Dávila Gómez, Hospital General Educational Heroes of the Baire, Cuba, E-mail: heenry@infomed.sld.cu


Introduction
The cancer is at the moment one of the illnesses that awake bigger interest among the investigators to be an important cause of morbility and of death in the world. THE cervical cancer is the third more frequent gynecological cancer in the world, with a frequency of 9,8% and it is considered that annually in the world they are diagnosed around 500 000 new cases of cancer cervical invader, of which the half is mortals [1]. In Cuba, this illness constitutes an important problem of health for its high indexes of morbi-mortality and emotional impact in the population. In some territories of the country, a stable tendency is observed while in other it spreads to the ascent of its incidence, like it is evidenced in an article of Padilla and collaborators [2] in Ciego de Ávila (2015), the same as in the Isle of Youth where growing values are reported in the last decade [3].
A series published by Lamb and García [4] in the town of San José of the Flagstones among 2011-2012 was also evidenced that it is happening a change in the age of appearance of this tumor type possibly related with the precocity of the first sexual relationships, the promiscuity and the concomitance of other factors of risk. This phenomenon has already been described by authors in diverse counties of the country like León Cruz [5] Rodríguez Salvá [6] and Martinez Pinillo [7].
The patients with lesion intraepithelial of low degree face minimum possibilities to develop a lesion cervical invader, as long as those with lesions of high degree are progression risk on high to cancer. In the handling of the women with NIC, the objective consists on preventing the possible progression to cancer invader without sobretratar the lesions with high regression probabilities [8]. Along the time different treatments and protocols have been proven with the objective of obtaining the best results in the control of this pathology; among these the ablative methods that destroy the lesion in situ and the split that extirpate it are. In the last years, a deep change has taken place in the handling of the pre-wicked processes of the uterine neck.
The cone with handle surgical electro (LEEP) it is an alternative in most from the cases to the cold cone with scalpel, with what a reduction of the bled intra operating has been obtained and of the post-surgical hemorrhage; with the rising reduction of the time of hospitalization or with ambulatory character, like in the context object of this investigation. The biggest difficulty attributed to the conization with handle of LEEP refers to the evaluation histological of the surgical borders for the thermal damage that produce [9]. The recurrence range or persistence of the NIC is located among 5-17%, independently of the type of elected therapy. The high indexes of persistent illness associate to lesions of big dimensions, commitment of glands endocervical, positive margins and continuous positivity to DNA of the virus of the human papilloma.
In the Isle of Youth, the behavior of the morbility and mortality for cervical cancer and the incidence of its lesions precursors constitutes a serious problem of health. With a global tendency to the increment in the last 15 years, in the triennium 2014-2016 40% of all the cases of the period 2003-2016 and 57% have been diagnosed in patient smaller than 30 years (data of the autor [3,10]) over dimensioned the problem to medical situations not habitual two or three decades behind, as the attention to pregnant and patient without satisfied parity.
For the context where this study the contribution of this investigation is developed it could constitute a vital tool in the taking of decisions before one of the most common dilemmas that faces to newspaper to a kindred doctor to the topic: when to decide for expectant behavior, re-of surgical section, state of the cervical channel, area was evaluated affected by lesion and persistence of the IVPH post-cone.
Prosecution of data: For the statistical analysis the applications Epidat 3.1 and SPSS-22 were used. The width and number of intervals for the analysis of the age were determined using the rule of Sturges. The description of categorical variables is carried out with absolute and relative frequencies in percentages. The relationships among categorical variables are analyzed by means of the comparison of proportions with the test of Chi-square of Pearson and the exact test of bilateral Fisher was used in the case of not being able to be applied the Chi-square test of Pearson. To determine the statistical significance 95%, it was used (p <0,05) according to Cornfield, being carried out an analysis initial univariate that also evaluated reasons of disparity (odds ratio). The variables that demonstrated significance were subjected to an analysis multivariate of Binary Logistical Regression, leaving of a maximum model with the variables and moving away variables for approach of statistical significance. The obtained prediction pattern was subjected safe against kindness of adjustment of Hosmer and Lemeshow, besides being determined its Coefficient of determination and the area under the Curve of ROC.

Analysis and discussion of the results
The distribution for age bracket shows like a similar distribution existed among the four strata, with slight prevalence of the groups among 36-41 years (27%) and bigger than 41 years (26%). however, the comparison among patient with and without alone residual lesion it showed significant statistical relationship in the patients bigger than 41 years (OR>8, p <0,05). The results of this investigation coincide with most of studies published regarding the age of the patients, with stockings that oscillate between 27 and 47 años [11]. The fact of finding a remarkable quantity of cases below 30 years (22%) it denotes the precocity with which they spread to appear these lesions precursors. Examples of this are works like those of Leguevaque et al. [12] (it mediates: 38 years); Lubrano et al. [13] (it mediates: 37,8) and Söderlund-Strand et al. [14] (media: 34 years). The basic explanation is related with the own natural evolution of the infection for the VPH considered necessary cause for the development of a lesion intraepithelial of uterine cervical. After the 30-35 years, the clearing capacity diminishes and the infection for the VPH persists in the cervical epithelium developing its capacity oncogenic and increasing the prevalence of NIC2 + that requires surgical treatment. 38% of the patients had a previous cytology to the conization with a lesion cervical epithelial of high degree and 29%, a lesion cervical epithelial of low degree. 19% of the patients had its last negative cytology and 5% only presented a cytology with cervical cancer. Several bibliographical revisions have valued the accuracy of the one sieved with conventional cytology comparing it with the diagnosis histological. Among 12 studies selected by their best methodology [15], the range of sensibility was of 30-87% and that of specificity of 86-100%. The notables' differences in the sensibility of the cytology among the different publications can be explained by the scarce reproducibility of the cytology or different biases. Some articles like the one presented by Carvajal et al. [16] only mentions a disagreement cytological of 24%, while others as Perrotta et al. [17] mention 52% of disagreement. In Cuba, a study of it Seasons I Lived and Carlos Moya et al. [18] in the Hospital University Martyrs of April 9" (Villa Clara) it showed that a direct relationship exists among the infection for VPH and the appearance of the lesions cervical intraepithelial, since in the patients' 72,6% the discovery cytological of the VPH existed, against alone 27,4% of patient with negative cytologists. Similar result shows Lamb Martínez et al. [4] in its study in the county of Mayabeque.
cone or hysterectomy. The study of these variables allows to deepen in the knowledge that every day arises in this respect, since they were few studies in the country and none deepens in the prediction diagnostics, which won't only offer a therapeutic contribution but also diagnosis of this pathology. From the methodological point of view, the present investigation will be good as starting point to other investigators to elaborate future studies related with this topic, and it would also allow to this institution to offer them more and better treatment alternatives to the patients that consult for this pathology, diminishing this way its relapse and the high rate of mortality for cancer of uterine neck and for ended, less economic impact on the costs hospital and better quality of the population's life.

Objectives
General: To identify relationship between the diagnosis of residual illness and clinical-epidemic factors of interest in patient with lesions cervical epithelial of high degree or micro invader that were conics in the Hospital General Educational Heroes of the Baire during the period 2014-2016.
Goals objectives: 1. to describe the distribution of variables as groups age, conization type, diagnosis cytology and time of study post-cone.
2. to identify the presence of factors spreading of residual lesion in the study sample.

Design methodological
It was carried out a prospective descriptive observational study to determine the statistical relationship between the diagnosis of residual illness and clinical-epidemic factors of interest in patient with lesions cervical epithelial of high degree that were conic in the Hospital General Educational Heroes of the Baire during the period 2014-2016. Universe and it Shows: The universe understood the 779 patients to who were practiced a conization by handle diathermic and it was obtained a lesion epithelial of high cervical degree or a carcinoma micro invader as a result in the period 2014-2016. For the conformation of the sample the range was calculated understood between the 25 and 75 percentile of the stocking of the age for the patients with residual lesion, considering that these 63 patients only represented 8% of the universe and the disproportion among patient con/sin residual lesion could affect the statistical significance. The sample was integrated by 428 patients: 63 with residual lesion and 365 without residual lesion. Exclusion approaches: Patient with more diagnosis to the stadium that were conic for confirmation histological or estadiamiento.
Gathering of data: The clinical histories of all studied patients, the cytology card, their images colposcópicas and the biopsy tickets were revised. Variables were analyzed as age, diagnosis initial cytological, diagnoses previous histological to the cone and definitive, conization type, time of evolution post-cone free of lesion, glandular lesion in cervical channel, extension of the lesion to the channel according to colposcopy and diagnosis cytological of IVPH confirmed by histology. Specifically, in the studied surgical specimen the state of the borders As for the parity, 39% of the patients had two children and similar percent (36%) they had a son, while the patient nulíparas only represented 9%. however, a statistical difference was only observed in patient with more than two children (OR=1,9 p=0,049).
The habit of smoking didn't show significant difference among patient with and without residual lesion, in spite of being present in 87 studied patients, with OR=1,7 and p=0,1115. 37% of the patients was conizadas for a previous biopsy with NIC2, while in 22% the biopsy a NIC3 reflected. In 29% he/she was not correlation cytological-colposcópica-histological. However, only in the patients with carcinoma in situ (OR: 2,8 p: 0,014) or carcinoma micro invader (OR: 3,4 p: 0,036) he/she was statistical difference. Diverse studies have demonstrated that even with the use of strict approaches of selection, around 10-20% of patient with confirmed histology of CIN2-3 in the biopsy directed by colposcopy before the surgery, residual CIN doesn't present in the definitive histology of the conization piece. In the study of Livasy et al. [19] the percentage of negative cones was of 13,8%, in the series of Ryu et al. [20] 17,7% and in that of Rodríguez-Manfredi et al. [21] 16%. 46% of the patients had a lesion with an area of 100-199mm 2 and 28% of the patients they had a lesion of 200-299mm 2 . The patients with lesions of 300mm 2 or they only represented less 5%. nevertheless, he/ she was statistical difference among patient with and without residual lesion in the patients with an area of more lesion at 199mm 2 (OR=2,6-4,5 p <0,05). 90% of the patients was conizadas for the method of handle diathermic (radiosurgery). In none of the cases with the method of cold scalpel was residual lesion.
With relationship to the diagnosis definitive histological, it is appreciated that almost 50% of the patients presented a NIC3 and 30%, a NIC2. In spite of it, only those that presented a carcinoma in situ (OR: 2,53 p=0,01) or a carcinoma microinfiltrante (OR: 6,42 p=0,00) they showed a different behavior statistically as for the presence or not of residual lesion. It was also observed as three of each four patients without residual lesion they present more than 24 months free of the illness and in the patients' 15%, this period was of 13-24 months.
In the consulted literature, the frequency of margins affections oscillates in 10,8-46% [22,23]. most of the studies demonstrate that the margins affections increase the risk of illness residual [24,25] significantly. In the study of Houfflin-Debargue et al. [26] the patients with positive margins were 36%, in the study of Serati et al. [27], 32% of the patients presented margins affections and it was found that this was the factor more important predictor of recurrent illness, the same as in the works of Prato [28] and Baloglu et al. [29].
In an analysis univariate of factors related with the surgical specimen, 16% of the studied patients had an infection for VPH diagnosed to the moment of the conization and 13% it maintained this infection during its evolution post-cone. It is attractive also that in 10% of the patients borders of surgical section were evidenced affected by lesion and in 9% of the patients the colposcopy showed that the lesion penetrated the channel endocervical. However, the variables that showed statistical significance were the presence of glandular lesion (OR: 3,5 p=0,0001), the borders of surgical section affected by lesion (OR: 4,3 p=0,0000) and the presence of area of transformation type 3 (OR: 5,0 p=0,0000), in growing order (Table 1).
When carrying out an analysis multivariate of logistical regression with the variables that showed statistical significance it was found that, of the studied factors, only the surgical borders affected by lesion (OR: 7,1), the carcinoma diagnosis in situ or microinfiltrante (OR:6,0), an area of lesion bigger 199 mm 2 (OR: 5,8) and the presence of glandular lesion (OR: 4,0) they behaved as factors predictors of residual lesion, when reflecting an OR>1 and a significance (p <0,05) ( Table 2).
The proposed pattern showed a good variability among the prospective value and observed for patient with and without residual lesion to the subjected being to the test of kindness of adjustment of Hosmer and Lemeshow, what demonstrates its validity predictor. This way, when calculating the probability of appearance of residual lesion in presence of the four factors predictors, a p=0,796 is obtained. that is to say, according to the proposed pattern a patient with carcinoma in situ or micro invader, with glandular lesion, a bigger area 199mm 2 and positive surgical borders have 79,6% of probability of having a residual lesion.