TEMPLATE DESIGN © Negative LLETZ following severe dyskaryosis: a curious phenomenon Üçyiğit A, Jones M H, Dutta A, El Sayed M, Dugmore W E, Thomas V, Carter P G Darent Valley Hospital, Dartford, Kent, United Kingdom. St George’s Hospital, London, United Kingdom Objectives Large loop excision of the transformation zone (LLETZ) is a standard treatment for suspected cervical intraepithelial neoplasia grade III and provides histological confirmation of the diagnosis. Since the introduction of LLETZ a worrying phenomenon has been observed, whereby there is negative histology on LLETZ despite a confirmed diagnosis of severe dyskaryosis on the referral cervical smear. The incidence of this problem has been reported as anywhere between 20% and 34% of all LLETZ biopsies regardless of the grade of referral cytology. 1,2 There is little available data for severe dyskaryosis specifically. The objective of this study was to identify the incidence of negative LLETZ following a cytological diagnosis and treatment of severe dyskaryosis, and to explore why this may occur. Methods A retrospective review of the electronic colposcopy database ‘View Point’ was conducted over a eight year period. The study was conducted in two clinical settings: a teaching hospital in London and a district general hospital in Kent, St. George’s Hospital (SGH), and Darent Valley Hospital (DVH) respectively. All women who had severe dyskaryosis on referral with a negative histology result after LLETZ were included. The incidence of negative LLETZ and the rates of negative and abnormal cytology after LLETZ were compared between the two centres. A supplementary retrospective study was undertaken in the district general hospital setting over the subsequent three years from the completion date of the main study (2008 to 2011 inclusive). Results A total of 62 patients with negative LLETZ were identified from a population of 1152 with severe dyskaryosis. Of these, 41 cases were at SGH, and 21 at DVH (6.6% vs. 4.0%) which was not statistically significant (Table 1). Table 2 shows the proportion of patients with negative cytology on follow-up: 85% vs. 62% (SGH vs. DVH). Conversely, table 3 shows the proportion of patients with abnormal cytology on follow-up: 10% vs. 5%, and further treatment was performed in 10% and 19% of patients at SGH and DVH respectively. Table 4 compares the incidence of negative LLETZ following a referral with severe dyskaryosis at DVH in the initial and supplementary studies. This was not found to be significantly different from the previous result (p=0.7). * Difference not significant at 5% level but significant at 6.6% (exact test) An explanation for negative LLETZ was identified in 5 cases: 4 cases of high endocervical disease were confirmed following hysterectomy, and one case of vaginal cancer was identified. No explanation was found for the remaining patients. Conclusions References The finding of negative LLETZ despite severe dyskaryosis on referral cytology is an uncommon, yet curious event. There was however no demonstrable difference in incidence between the teaching hospital and district general hospital settings and there appears to be a low risk of missing malignancy. A small proportion of patients demonstrated recurrent abnormal cytology on follow-up. This lack of correlation between histological and cytological results may be explained by current histological sampling techniques (how the specimens are sliced), where small-volume high grade lesions may not be revealed. It is interesting to note that the findings of the supplementary study performed three years after the initial work showed a remarkably similar incidence of negative LLETZ following referral with severe dyskaryosis. This consistency of findings makes it still the more difficult to explain how this clinical situation arises. Despite the recommendation that nearly all LLETZ specimens should contain CIN, this has not been achieved in the majority of colposcopy units. 3 What follow-up regime, and ultimately treatment is best employed in these cases requires further investigation. 1. Skehan M, Soutter WP, Lim K, Krausz T, Pryse- Davies J. Reliability of colposcopy and directed punch biopsy. Br J Obstet Gynaecol Sep;97(9): Lopes A, Pearson SE, Mor-Yosef S, Ireland D, Monaghan JM. Is it time for a reconsideration of the criteria for cone biopsy? Br J Obstet Gynaecol.1989 Nov;96(11): Semple D, Saha A, Maresh M. Colposcopy and treatment of cervical intra-epithelial neoplasia: are national standards achievable? Br J Obstet Gynaecol Apr;106(4): Acknowledgement: We would like to thank Dr J J Jones for his help with statistical analysis. Table 1: Negative LLETZ after severe dyskaryosis HospitalNegative LLETZConfidence limits SGH n = 416.6%(4.6 – 8.5) DVH n = 214%(2.3 – 5.7) Difference*2.6%(-0.2 – 5) Table 2: Negative smear after LLETZ HospitalNegative smearConfidence limits SGH85%(71 – 94) DVH62%(38 – 82) Difference23%(0 – 49) Table 3: Abnormal cytology after LLETZ HospitalAbnormal smearConfidence limits SGH10%(3 – 23) DVH5%(0.1 – 24) Difference5%(-13 – 17) Table 4: Supplementary study StudyNegative LLETZConfidence limits DVH %(2.3 – 5.7) DVH n = 7/232 3%(1 – 5)) Difference-1%(+2 – -4)