What should be the goal for future development of colposcopy? Cons and pros of sensitivity and specificity.

PURPOSE: To discuss what features of colposcopy should be developed for the future in different settings. RESULT: There are cons and pros of aiming sensitivity, negative predictive value and specificity and positive predictive value. In case of diagnosis and intervention, methods increasing the specificity and positive predictive value will help to decrease unnecessary interventions. Besides, HPV test is highly sensitive and has a good negative predictive value. It is usually available before colposcopy. CONCLUSION: Colposcopy can be used in a screening or diagnostic/interventional scenario. Aims to improve sensitivity or specificity may change according to the aim of colposcopy. However, in the presence of highly sensitive tests which are performed before colposcopy, first goal to improve for colposcopy can be specificity and positive predictive value.

Clinical relevance of objectifying colposcopy.

PURPOSE: To evaluate the clinical value of four objective colposcopic criteria inner border, ridge sign, cuffed crypt openings and rag sign to diagnose cervical intraepithelial neoplasia grade 2 or worse (CIN 2+), using video exoscopy and to compare it to subjective graduating signs. METHODS: Retrospective evaluation of video recordings of 444 patients, referred for diagnostic colposcopy, who underwent cervical biopsies, and if indicated loop excisions. Most severe histological diagnosis was recorded. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LR) with 95% confidence interval, for CIN 2+ were calculated. RESULTS: Single biopsy, two biopsies and magnification-guided loop excision were performed in 60.8, 39.2 and 70.5% of patients, respectively. Sensitivity, specificity, PPV and NPV to detect CIN 2+ were 19.3, 99.2, 98.3 and 35.8%, for inner border sign; 53.1, 93.5, 94.7 and 47.6%, for ridge sign; 51.5, 84.9, 88.2, and 44.3%, for cuffed crypt openings, and 40.7, 96.4, 96.1 and 42.5%, for rag sign, respectively. The positive likelihood ratio (LR+) was 26.7 and the negative likelihood ratio (LR-) was 0.81, for inner border sign; 8.2 and 0.5, for ridge sign; 3.41 and 0.57 for cuffed crypt openings; and 11.3 and 0.62 for rag sign, respectively. 90% of CIN 2+ had at least one objective sign. Combination of any two objective signs significantly increased the LR of the presence of CIN 2+, and was clinically superior to any combination of graduating signs. CONCLUSION: Objective colposcopic criteria are clinically useful and significantly associated with CIN 2+.

Radical vaginal trachelectomy after laparoscopic staging and neoadjuvant chemotherapy in women with early-stage cervical cancer over 2 cm: oncologic, fertility, and neonatal outcome in a series of 20 patients.

OBJECTIVES: The aim of the study was to assess oncologic and fertility outcome of treatment in patients with cervical cancer of more than 2 cm seeking parenthood. METHODS: The regimen consisted of laparoscopic lymphadenectomy as a staging procedure to confirm no lymph node metastases before neoadjuvant chemotherapy (NACT) consisting of 2 or 3 cycles of paclitaxel/ifosfamide/cisplatin followed by radical vaginal trachelectomy (RVT). Oncologic and fertility outcome was evaluated prospectively. RESULTS: Twenty women were enrolled up to now. The mean age was 32 years (range, 26-41 years), and mean tumor size was 3 cm (range, 2.1-5.0 cm). Lymphadenectomy was performed before NACT without complications. During NACT, hematologic toxicity grade 3 was observed in 2 of 20 patients, and renal toxicity grade 3 in 1 of 20 patients. Radical vaginal trachelectomy was performed in 18 women until now with 2 intraoperative complications (ureter injury and injury of internal iliac vein). There were no severe postoperative or long-term complications. Complete pathologic remission was found in 9 of 18 patients. In 2 of 18 patients, chemoradiation was recommended because of insufficient pathologic response in the RVT specimen. After a mean follow-up of 23 months (range, 1-88 months), 1 relapse was observed. After RVT, 7 women tried to conceive until now. Seven pregnancies occurred in 5 women. Four children were born, 2 of whom were premature (31 weeks 2 days and 33 weeks 4 days of gestation); 1 pregnancy is ongoing. CONCLUSIONS: Laparoscopic lymphadenectomy followed by NACT and RVT in pN0 patients with cervical cancer of more than 2 cm seems to be an oncologically safe procedure with promising fertility outcomes.

A multicentric randomized study comparing two techniques of magnification assisted loop excision of high-grade cervical intraepithelial neoplasia: video exoscopy and colposcopy.

PURPOSE: To compare loop excisions of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) under video exoscopy, or colposcopic guidance, with respect to safety and effectiveness. METHODS: Prospective multicentric randomized trial of 300 patients, undergoing loop excision for CIN 2+ either under video exoscopy (group A) or colposcope (group B) guidance. Intra- and post-operative complications, resection margins, and removed cervical volume in both groups were evaluated. RESULTS: 19.3 % of patients in video exoscopy group and 15.5 % in colposcopy group (p = 0.67) had transformation zone (TZ) 3. 45/151 (29.8 %) of group A patients and 48/149 (32.2 %) of group B patients underwent top-hat procedure, i.e., one superficial excision followed by one deeper removal of the endocervical tissue (p = 0.74). There was no difference in intra- and post-operative complications in the two groups. Positive endocervical resection margins (R0) were 9.9 % in video exoscopy group and 8.7 % in colposcopy group, respectively. Unclear endocervical resection margins (Rx) were 2.0 % in both groups. Mean total excised cervical volume was 1.20 cubic centimeter (cc³) in group A, and 1.24 cc³ in group B, respectively. Recurrent disease occurred in 2.3 % of patients at 6 months follow-up. CONCLUSION: Magnification assisted loop excision of CIN 2+ is equally effective and safe under colposcopic and video exoscopy guidance. The latter technique could potentially offer an alternative treatment of CIN 2+ lesions for doctors unfamiliar with colposcope.

Validity of the colposcopic criteria inner border sign, ridge sign, and rag sign for detection of high-grade cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate the association of three pathognomonic criteria, inner border, ridge sign, and rag sign with high-grade cervical intraepithelial neoplasia (CIN) using video exoscopy. METHODS: Retrospective evaluation of video recordings of 335 patients, referred for diagnostic colposcopy, who underwent cervical biopsies, and, if indicated loop excisions, was performed. The most severe histologic diagnosis was recorded. Sensitivity, specificity, positive, negative predictive value, and likelihood ratios for high-grade CIN were calculated. RESULTS: In 285 patients (85%), a single colposcopy directed biopsy was taken; 50 patients (15%) underwent two biopsies. One hundred sixty-two patients (48%) underwent subsequent magnification-guided loop excision. Sensitivity, specificity, positive predictive value, and negative predictive value of the inner border to detect high-grade CIN were 20%, 99%, 97.9%, and 34.8%, respectively. The positive likelihood ratio (LR+) was 20.3 and the negative likelihood ratio (LR-) was 0.81. Sensitivity, specificity, positive predictive value, and negative predictive value of the ridge sign to detect high-grade CIN were 52.5%, 96.4%, 96.8%, and 46.6%, respectively. The LR+ ratio was 13.2 and the LR- ratio was 0.49. Sensitivity, specificity, positive predictive value, and negative predictive value of the rag sign to detect high-grade CIN were 38.4%, 96%, 95.7%, and 40.2%, respectively. The LR+ ratio was 9.7 and the LR- ratio was 0.6. Only the ridge sign showed a correlation with young age. Presence of any two signs significantly increased the LR of the presence of high-grade CIN. CONCLUSION: The inner border, ridge sign, and the newly defined rag sign are objective, effective colposcopic signs and are significantly associated with high-grade CIN.

Laparoscopic lymph node dissection should be performed before fertility preserving treatment of patients with cervical cancer.

OBJECTIVE: The aim of this study is to assess our results of treatment of women with stage I cervical cancer>2 cm in diameter seeking fertility preservation. Treatment consisted of Laparoscopic Pelvic and Paraaortic Lymphadenectomy (LPPLND), and when no nodal metastasis was detected, neoadjuvant chemotherapy (NACT) followed by radical vaginal trachelectomy (RVT). Patients with positive lymph nodes underwent primary chemoradiation. METHODS: A cohort of women younger than 40 years of age with stage I disease>2 cm who underwent LPPLND and either NACT and RVT or chemoradiation. Oncological outcome was evaluated prospectively. RESULTS: Eighteen women were eligible for this study. Twelve (67%) women were diagnosed with metastasis in one or more pelvic and/or paraaortic lymph nodes, and thus received primary chemoradiation. After a mean follow-up of 25.5 months, three out of these 12 women (25%) developed a recurrence. Six women (33%) underwent NACT and RVT. Three patients experienced complete response to NACT and three patients showed more than 50% tumor size reduction. After a mean follow-up of 30.6 months all six women are free of recurrence. One patient delivered a healthy infant. CONCLUSIONS: Staging LPPLND allows separating patients in high or low recurrence risk groups. NACT and RVT seem to be safe for women with completely staged stage I cervical cancer>2 cm in diameter, whereas even after primary chemoradiation, patients with positive lymph nodes experienced recurrence. Therefore, selection of patients with stage I cervical carcinoma>2 cm, eligible for fertility preservation should include histopathologic evaluation of lymph node status before any further treatment.

Eutopic endometrium from women with endometriosis does not exhibit neurotrophic properties.

The role of neurotrophins in eutopic endometrium from endometriosis-patients was investigated in a prospective study using immunofluorescence-staining, Western blot and a neuronal growth assay. The nerve growth factor is expressed in primary endometrial cell culture from women with and without endometriosis. Western blot analysis of endometrial biopsies or uterine fluid from patients with and without endometriosis shows no difference in the neurotrophin expression. We could not find a difference between patients with and without endometriosis with regards to the neurite outgrowth of sensory ganglia when treated with conditioned cultured medium or uterine fluid. This result refutes the assumed neurotrophic properties of eutopic endometrium of patients with endometriosis.

Imbalance between sympathetic and sensory innervation in peritoneal endometriosis.

To investigate possible mechanisms of pain pathophysiology in patients with peritoneal endometriosis, a clinical study on sensory and sympathetic nerve fibre sprouting in endometriosis was performed. Peritoneal lesions (n=40) and healthy peritoneum (n=12) were immunostained and analysed with anti-protein gene product 9.5 (PGP 9.5), anti-substance P (SP) and anti-tyrosine hydroxylase (TH), specific markers for intact nerve fibres, sensory nerve fibres and sympathetic nerve fibres, respectively, to identify the ratio of sympathetic and sensory nerve fibres. In addition, immune cell infiltrates in peritoneal endometriotic lesions were analysed and the nerve growth factor (NGF) and interleukin (IL)-1ß expression was correlate with the nerve fibre density. Peritoneal fluids from patients with endometriosis (n=40) and without endometriosis (n=20) were used for the in vitro neuronal growth assay. Cultured chicken dorsal root ganglia (DRG) and sympathetic ganglia were stained with anti-growth associated protein 43 (anti-GAP 43), anti-SP and anti-TH. We could detect an increased sensory and decreased sympathetic nerve fibres density in peritoneal lesions compared to healthy peritoneum. Peritoneal fluids of patients with endometriosis compared to patients without endometriosis induced an increased sprouting of sensory neurites from DRG and decreased neurite outgrowth from sympathetic ganglia. In conclusion, this study demonstrates an imbalance between sympathetic and sensory nerve fibres in peritoneal endometriosis, as well as an altered modulation of peritoneal fluids from patients with endometriosis on sympathetic and sensory innervation which might directly be involved in the maintenance of inflammation and pain.

Influence of nerve growth factor in endometriosis-associated symptoms.

To investigate the role of the nerve growth factor (NGF) in the development of dysmenorrhea/pelvic pain in patients with endometriosis, we performed a prospective, clinical, blind study. Peritoneal fluids (PFs) were obtained from patients with histologically proven endometriosis. Patients with endometriosis were divided into 7 different groups depending on their preoperative pain score and symptomatology: patients with no pain, patients with minimal pain (dysmenorrhea, pelvic pain, or both), and patients with severe pain (dysmenorrhea, pelvic pain, or both) and were used for the neuronal growth assay with cultured chicken dorsal root ganglia (DRG) and for Western blot analyses. Dorsal root ganglia were stained with anti-calcitonin gene-related peptide (CGRP) and anti-growth-associated protein 43 (GAP 43). Peritoneal fluids from patients with endometriosis induce neurite outgrowth. There was no significant difference in the outgrowth between the 7 pain groups. Western blot analyses showed a moderate NGF expression in the PFs from patients with endometriosis, without significant differences in the 7 pain groups. The present study suggests that the neurotrophic properties of endometriotic tissues are endometriosis- and not pain-associated.