SIIV position paper: clinical approach to vulval diseases. Need for quality standards.

This paper summarizes the position of the Italian Society of Vulvology on the clinical approach to vulval disease. A thorough history (general medical, gynaecological, and vulval history) is essential for a successful and fruitful vulvological examination. Characteristics of pruritus (itch) and pain, that are the two main vulval symptoms, should be collected and reported with precision, according to duration, temporal course, location, provocation, and intensity. Physical examination must consider both the general condition of the patient and the specific vulval region, that must be examined following a standardized methodology. The physical examination of the vulva is carried out with naked eye and adequate natural or halogen lighting. The subsequent use of instrumental magnification can be considered on particular parts of skin/mucosa, already highlighted with the first inspection. Also, palpation is essential, allowing to appreciate physical features of vulval lesions: consistency, surface, soreness, adherence to underlying plans. Finally, the five-step approach of the International Society for the Study of Vulvo-vaginal Disease about Terminology and Classification of Vulvar Dermatological Disorders (2012) is summarized. A vulval biopsy may be useful in the following situations: when clinical diagnosis is uncertain, lesion not responding to treatment; histologic confirmation for a clinical diagnosis and exclusion or confirmation of a suspected neoplastic intraepithelial or invasive pathology.

Results of the First Italian External Quality Assurance Scheme for somatic EGFR mutation testing in non-small-cell lung cancer.

INTRODUCTION: The Italian Association of Medical Oncology (AIOM) and the Italian Society of Pathology and Cytology organized an external quality assessment (EQA) scheme for EGFR mutation testing in non-small-cell lung cancer. METHODS: Ten specimens, including three small biopsies with known epidermal growth factor receptor (EGFR) mutation status, were validated in three referral laboratories and provided to 47 participating centers. The participants were requested to perform mutational analysis, using their usual method, and to submit results within a 4-week time frame. According to a predefined scoring system, two points were assigned to correct genotype and zero points to false-negative or false-positive results. The threshold to pass the EQA was set at higher than 18 of 20 points. Two rounds were preplanned. RESULTS: All participating centers submitted the results within the time frame. Polymerase chain reaction (PCR)/sequencing was the main methodology used (n = 37 laboratories), although a few centers did use pyrosequencing (n = 8) or real-time PCR (n = 2). A significant number of analytical errors were observed (n = 20), with a high frequency of false-positive results (n = 16). The lower scores were obtained for the small biopsies. Fourteen of 47 centers (30%) that did not pass the first round, having a score less than or equal to 18 points, used PCR/sequencing, whereas 10 of 10 laboratories, using pyrosequencing or real-time PCR, passed the first round. Eight laboratories passed the second round. Overall, 41of 47 centers (87%) passed the EQA. CONCLUSION: The results of the EQA for EGFR testing in non-small-cell lung cancer suggest that good quality EGFR mutational analysis is performed in Italian laboratories, although differences between testing methods were observed, especially for small biopsies.

Vulvar paget disease: a large single-centre experience on clinical presentation, surgical treatment, and long-term outcomes.

OBJECTIVE: Our aim was to add information to the current literature on vulvar Paget disease by reviewing a consistent number of patients who have been all diagnosed, treated, and followed up by the same group of physicians at a single medical institution. METHODS: Clinical, surgical, histological, and follow-up data of 34 patients (mean [SD] age at diagnosis = 68.7 [10.1] years) with vulvar Paget disease were reviewed during a 27-year period. RESULTS: Primary symptoms were itching (76.5%) and burning (58.8%). Clinical manifestations were present for a mean (SD) of 17.8 (7.2) months before the diagnosis was made. Multifocal lesions were observed in 17 patients (50%) and were associated with a delay in diagnosis exceeding 12 months (p = .03). Of the patients, 10 (29.4%) presented a history of malignancy in other sites. Surgery with various extent of resection was performed as primary treatment in all patients. Definitive histological examination revealed positive surgical margins in 15 cases (44.1%), stromal invasion in 4 (11.7%), and associated adenocarcinoma in 2 (5.9%). Of the patients, 6 (17.6%) underwent reconstructive technique at their primary surgery or radicalization. During a mean (SD) follow-up of 76.9 (51.3) months, 15 patients (44.1%) experienced local recurrence (1 recurrence in 29.4%, 2 recurrences in 5.9%, and 3 recurrences in 8.8%). First recurrence appeared after a mean (SD) time of 45.7 (25.1) months and was associated with multifocal lesions (p = 0.005) and surgical margins involvement (p = 0.03). One patient (2.6%) died of the disease. CONCLUSIONS: Vulvar Paget disease is a chronic disease with high recurrence rate and low mortality. Early diagnosis, minimal surgery with free margins, and long-term follow-up are the cornerstones of treatment.

Mini-laparotomy versus vaginal surgery for class II-III obese patients with early-stage endometrial cancer.

AIM: To compare minilaparotomic and vaginal surgery in selected obese patients with early-stage endometrial cancer at high surgical risk. PATIENTS AND METHODS: Data of 37 consecutive class II-III obese patients submitted to minilaparotomic surgery were retrospectively reviewed. Thirty-seven women matched for demographic characteristics, BMI and stage of disease submitted to vaginal surgery in the same period comprised the control group. RESULTS: No difference was observed concerning intra- and postoperative data among the two groups. The patients who were submitted to general anesthesia exhibited a larger use of supplemental drugs for pain control (p>0.01), a higher incidence of thromboembolic events (p>0.005) and a longer hospitalization (p>0.02). No statistical difference was observed in terms of pattern of recurrence, disease-free survival and overall survival between the two groups of patients. CONCLUSION: Obese patients with endometrial cancer unfit for vaginal surgery can be safely managed through mini-laparotomy with the same surgical and oncological outcomes.

DNA ploidy is stronger than lymph node metastasis as prognostic factor in cervical carcinoma: 10-year results of a prospective study.

INTRODUCTION: To improve the outcome of patients with cervical cancer, a more accurate prognostic assessment is essential. The aim of this study was to evaluate the role of tumor DNA ploidy as an independent prognostic factor in cervical carcinoma. Furthermore, we investigated whether the presence of lymph node metastasis may have a different clinical impact according to ploidy status. METHODS: In a long-term prospective study, DNA ploidy was evaluated by flow cytometry from fresh tumor samples from 136 patients with cervical cancer who underwent surgery. Ploidy, lymph node metastasis, and other classical parameters were analyzed in relation to the length of disease-specific survival. Treatment modalities did not differ between patients with diploid tumors and patients with aneuploid tumors. RESULTS: DNA aneuploidy was found in 52 patients (38.2%). Patients with DNA-aneuploid tumors had a significantly reduced disease-specific survival (P = 0.003). Overall, the 10-year survival probability was 54% for patients with DNA-aneuploid tumors and 80% for patients with DNA-diploid tumors. Among 64 patients with International Federation of Gynecologists and Obstetricians stage I disease, the 10-year survival rates were 38.7% for the patients with DNA-aneuploid tumors and 86.3% for those with DNA-diploid tumors (P = 0.003). Overall, diploid tumors with lymph node metastasis did significantly better than aneuploid tumors with lymph node metastasis (P = 0.05). Among the patients with International Federation of Gynecologists and Obstetricians stage I disease, there was a highly significant difference between patients with diploid node-positive tumors and patients with aneuploid node-positive tumors, with no deaths from the disease in the former group in contrast with the worst outcome in the latter group (P = 0.005). By multivariate analysis, pathologic tumor stage, lymph vascular invasion, and tumor ploidy were significant and independent parameters, whereas lymph node metastasis yielded no independent information. CONCLUSIONS: DNA ploidy was an independent prognostic factor in cervical carcinoma. Presence of lymph node metastasis may not always have the same impact on survival but may vary according to DNA ploidy of the primary tumor.

KRAS mutations testing in colorectal carcinoma patients in Italy: from guidelines to external quality assessment.

BACKGROUND: Monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) have been approved for the treatment of patients with metastatic colorectal carcinoma (mCRC) that do not carry KRAS mutations. Therefore, KRAS testing has become mandatory to chose the most appropriate therapy for these patients. METHODOLOGY/PRINCIPAL FINDINGS: In order to guarantee the possibility for mCRC patients to receive an high quality KRAS testing in every Italian region, the Italian Association of Medical Oncology (AIOM) and the Italian Society of Pathology and Cytopathology -Italian division of the International Academy of Pathology (SIAPEC-IAP) started a program to improve KRAS testing. AIOM and SIAPEC identified a large panel of Italian medical oncologists, pathologists and molecular biologists that outlined guidelines for KRAS testing in mCRC patients. These guidelines include specific information on the target patient population, the biological material for molecular analysis, the extraction of DNA, and the methods for the mutational analysis that are summarized in this paper. Following the publication of the guidelines, the scientific societies started an external quality assessment scheme for KRAS testing. Five CRC specimens with known KRAS mutation status were sent to the 59 centers that participated to the program. The samples were validated by three referral laboratories. The participating laboratories were allowed to use their own preferred method for DNA extraction and mutational analysis and were asked to report the results within 4 weeks. The limit to pass the quality assessment was set at 100% of true responses. In the first round, only two centers did not pass (3%). The two centers were offered to participate to a second round and both centers failed again to pass. CONCLUSIONS: The results of this first Italian quality assessment for KRAS testing suggest that KRAS mutational analysis is performed with good quality in the majority of Italian centers.

Smooth muscle cells, dendritic cells and mast cells are sources of TNFalpha and nitric oxide in human carotid artery atherosclerosis.

INTRODUCTION: In atherogenesis, dendritic cells, beside presenting antigens, may be sources of tumour necrosis factor (TNF)alpha and nitric oxide (NO), together with mast cells and smooth muscle cells. MATERIAL AND METHODS: We have looked at the expression of TNFalpha and inducible NO synthase (iNOs) by these cells by affinity cytochemistry in autoptical specimens from normal carotid arteries and not ruptured, hemorrhagic or calcified atheromata. RESULTS: Round to dendritic, major histocompatibility complex class II molecules (MHC-II+) cells and avidin-labeled mast cells were rare in normal arteries and significantly more numerous in atheromata. Many MHC-II+ cells expressed S-100 antigen; while a few were positive for phalloidin; appreciable fractions of these cells were immunoreactive for TNFalpha and iNOs, both in control specimens and atheromata. The fraction of mast cells labeled for iNOs was significantly lower in atheromata than in controls. Phalloidin positive cells were the most abundant cell type in the normal intima and atheromata; the fractions of these cells labeled for TNFalpha and iNOs were significantly higher in atheromata than in controls. Very few of these cells were also labeled for MHC-II. Computerized image analysis confirmed that the amounts of iNOs and TNFalpha were higher in atheromata than in controls. The increase in TNFalpha in atheromata was also confirmed by western blot. CONCLUSIONS: Dendritic cells and mast cells can participate to the generation of TNFalpha and NO in the normal arterial wall and in atheromata, but myointimal cells are candidates as major sources of these molecules.

Ten-year results of a prospective study on the prognostic role of ploidy in endometrial carcinoma: dNA aneuploidy identifies high-risk cases among the so-called 'low-risk' patients with well and moderately differentiated tumors.

BACKGROUND: To improve the outcome of endometrial cancer patients, a more accurate prognostic assessment is mandatory. The aims of the study were to evaluate the role of flow cytometric DNA ploidy as an independent prognostic factor in patients with endometrial cancer and to verify if ploidy was able to distinguish patients with different prognosis into homogeneous subgroups for grade of differentiation and stage. METHODS: In a prospective study, DNA ploidy was evaluated from fresh tumor samples in 174 endometrial cancer patients who underwent surgery as the first treatment. Ploidy, as well as classical parameters, were analyzed in relation to the length of disease-free survival and disease-specific survival. RESULTS: DNA aneuploidy was found in 49 patients (28.2%). Patients with DNA-aneuploid tumors had a significantly reduced disease-free interval and disease-specific survival (P < .0001). The 10-year survival probability was 53.2% for DNA-aneuploid patients and 91.0% for patients with DNA-diploid tumors. By multivariate analysis DNA-aneuploid type was the strongest independent predictor of poor outcome, followed by age and stage. Patients with DNA-aneuploid tumor had a significantly higher risk ratio for recurrence (5.03) and death due to disease (6.50) than patients with DNA-diploid tumors. Stratification by DNA-ploidy within each group by grade of differentiation allowed identification of patients with significantly different outcome. In grade 2 tumors, 10-year survival was 45.0% in aneuploid cases and 91.9% in diploid cases (P < .0001). Patients with advanced-stage (>I) diploid tumor did significantly better than patients with stage I aneuploid tumor (P = .04). CONCLUSIONS: The presence of DNA-aneuploid type in endometrial cancer identifies high-risk cases among the patients considered 'low risk' according to stage and grade of differentiation.

Vaginal hysterectomy and abdominal hysterectomy for treatment of endometrial cancer in the elderly.

OBJECTIVE: The purpose of this study was to analyze the outcome of vaginal and abdominal hysterectomy for treatment of endometrial cancer in elderly patients. METHODS: In a retrospective series of 171 patients with age > or =70 years and at stages I-III, we evaluated operative and hospitalization data, as well as morbidity, mortality, and long-term survival associated with vaginal and abdominal hysterectomy. A total of 128 patients were operated on with vaginal hysterectomy and 43 cases underwent abdominal hysterectomy. RESULTS: Medically compromised patients were significantly more frequent in the vaginal surgery group (P = 0.01). Overall, the 10-year disease-specific survival rates after vaginal and abdominal hysterectomy were 80% and 78%, respectively (P = n.s.). Limiting the analysis to stage I (130 patients), 10-year disease-specific survival was 83% in 95 women operated on by the vaginal route and 84% in 35 patients operated by the abdominal approach (P = n.s.). Patients in the vaginal surgery group had a significantly shorter operative time (P = 0.01), less blood loss (P < 0.05), and were discharged earlier (P < 0.05). Severe complications occurred in 5.4% of the vaginal and in 7.0% of the abdominal procedures. Perioperative mortality was zero after vaginal hysterectomy and 2.3% after abdominal hysterectomy, respectively. CONCLUSIONS: Vaginal hysterectomy showed a high cure rate, shorter operative time, less blood loss, reduced morbidity, and no mortality and therefore may be considered the elective approach for treatment of elderly patients with endometrial cancer.

Frequent loss of expression of the cyclin-dependent kinase inhibitor p27(Kip1) in estrogen-related Endometrial adenocarcinomas.

PURPOSE: p27(Kip1) is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. Low levels of p27 are associated with poor prognosis in a variety of gynecological tumors, including breast, ovarian, and cervical carcinomas. The role of p27 in endometrial cancer remains controversial. EXPERIMENTAL DESIGN: In the present study, p27 protein expression was investigated by immunohistochemistry in a series of 217 endometrial adenocarcinomas and, where present, in synchronous normal endometrium, simple and complex hyperplasia (with or without atypia), and cystic atrophy. The relationship between p27 expression and clinical outcome was also evaluated. RESULTS: Immunohistochemical analysis revealed a significant loss of p27 expression from normal (33%) through hyperplastic endometrium (50%) to endometrial adenocarcinomas (71%; P

Vulvar carcinoma associated with lichen sclerosus. Experience at the Florence, Italy, Vulvar Clinic.

OBJECTIVE: To compare demographic and clinical characteristics of patients with lichen sclerosus (LS)-associated squamous cell carcinoma (SCC) of the vulva with those of patients with tumors not histologically associated with LS in a series of patients with vulvar SCC not HPV correlated. STUDY DESIGN: We retrospectively reviewed histologic specimens and clinical files of all vulvar SCCs referred to the Vulvar Clinic, University of Florence, Florence, Italy, since 1990. RESULTS: Twenty-five out of the 72 cases in this study (34.7%) were LS associated. Among these cases, 8 (32%) were diagnosed with LS before occurrence of the cancer and received treatment for the disease. In 17 cases the diagnosis of LS was simultaneous with that of SCC; in 13 cases the diagnosis was achieved by clinical examination and confirmed afterwards histologically. In 4 cases this was confirmed only by means of histologic examination. The shared profile of patients with LS-associated vulvar SCC was a subject (mean age, 72 years) seldom with a past medical history of vitiligo (16% of cases), with invasive cancer (92% of cases), clinically characterized by an exophitic tumor (73%), seldom ulcerated (18%) or showing hyperkeratosis (9%). Labia majora (32%), labia minora (27%) and vestibule (23%) were the most frequently involved sites. In most cases (80%) the cancer was limited to 1/3 of the vulvar region. An itch was the most frequent symptom. However, for all of these variables, no overall statistically significant difference was found with patients who had SCCs not associated with LS. CONCLUSION: The experience of the Vulvar Clinic, University of Florence, confirms the suggested role of LS as a possible precursor of vulvar carcinoma since 32% of our cases not HPV related were LS associated. We demonstrated that the profile of patients with LS-associated cancer does not differ from that of patients with cancer not associated with LS, excluding HPV-related cases. The existence of accessory conditions, probably needed to promote the progression from LS to cancer in a minority of subjects remains to be established.