Luis M. Puig-Tintoré

p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas.

Two types of vulvar squamous cell carcinomas (VSCCs) are recognized according to their relationship to human papillomavirus (HPV). Basaloid or warty carcinomas are considered HPV-associated tumors, whereas differentiated keratinizing neoplasms are considered non-HPV–associated. Recently, immunohistochemical detection of p16 and p53 has been proposed to differentiate these 2 types of VSCCs. We conducted a histologic study with immunohistochemical evaluation of p16 and p53 and HPV detection and typing by polymerse chain reaction using 2 different sets of primers in 92 cases of VSCCs to evaluate the usefulness of immunohistochemistry in the classification of VSCCs and to describe the clinico-pathologic characteristics of both types of VSCCs. HPV was detected in 16/92 (17.4%) specimens, HPV16 being identified in 75% of positive cases. A significant number of discrepancies between histology and HPV detection were observed, with 37.5% of HPV-positive tumors being keratinizing and 9.2% of HPV-negative carcinomas showing basaloid or warty features. Diffuse positivity for p16 and p53 was observed in 100% and 6.2% of HPV-positive tumors and in 2.3% and 64.5% of HPV-negative neoplasms, respectively. The sensitivity and specificity of p16 immunostaining to detect HPV-associated carcinomas (100% and 98.7%, respectively) were better than those of histologic criteria (93.8% and 35.5%) and of p53 negative stain (62.5% and 93.4%). Vulvar intraepithelial neoplasia grade 3 of basaloid/warty type was identified in 53.8% HPV-positive tumors, including 3 keratinizing tumors. All these cases were p16 positive and p53 negative. Vulvar intraepithelial neoplasia grade 3 of differentiated type was observed in 45.6% of HPV-negative cases; 90.8% of them were positive for p53 but all were negative for p16. No differences in age, stage, or development of recurrence were observed between HPV-positive and negative tumors. In summary, the current morphologic criteria to discriminate HPV-positive and negative VSCCs have a significant overlap. Immunostaining for p16 is a reliable marker for HPV-positive VSSCs, which improves the results of histologic classification.

Coverage and Factors Associated With Cervical Cancer Screening: Results From the AFRODITA Study: A Population-Based Survey in Spain

Objective. To quantify the coverage and monitor the factors associated with opportunistic cervical cytological screening in Spain. Materials and Methods. Population-based survey of selected women through the Access Panel technique representative of the general population. A total of 6,852 women (60%) replied to the questionnaire; 981 (14.3%) were excluded from the analysis because they did not meet the screening criteria. Data were adjusted for regions, age group, socioeconomic level (SEL), and municipality size. Moreover, information was collected on preventive gynecological revisions received. Categorical variables were evaluated through the &khgr;2 test of heterogeneity or through a liner test for trend. Multivariate prevalence odds ratios were used to identify statistically significant determinants of screening using logistic regression modeling. Results. The percentage of women 18 to 65 years old with a Pap smear within the last 3 years was 75.6%. Insufficient coverage was observed in women older than 55 years (66%), who live in rural areas (66%), with lower SEL (65%), and in some regions (61%-66%). The factors positively associated with screening were age 26 to 55 years, certain regions, higher SEL, larger municipality size, ever being pregnant, early age at first sexual intercourse, knowledge about cervical cancer and human papillomavirus, and, very strongly, ever use of contraceptive methods. An overuse of cytology can be assumed, as a result of opportunistic screening. Conclusions. In Spain, the coverage of cytological screening reached 75% of the population, but with inefficiencies in some aspects. To rationalize its use, the Spanish consensus screening protocol must be followed.

Papillomavirus research update: highlights of the Barcelona HPV 2000 international papillomavirus conference

The 18th international papillomavirus conference took place in Barcelona, Spain in July 2000. The HPV clinical workshop was jointly organised with the annual meeting of the Spanish Association of Cervical Pathology and Colposcopy. The conference included 615 abstracts describing ongoing research in epidemiology, diagnosis/screening, treatment/prognosis, immunology/human immunodeficiency virus, vaccine development/trials, transformation/progression, replication, transcription/translation, viral protein functions, and viral and host interactions. This leader summarises the highlights presented at the conference (the full text of the abstracts and lectures can be found at www.hpv2000.com). Relevant material in Spanish can be found at www.aepcc.org.

Epidemiology and cost of treatment of genital warts in Spain

BACKGROUND Genital warts (GW) are common and increasing in young people. Ninety percent of GW are due to Human Papillomavirus (HPV) types 6 and 11. The objective of this study was to assess the epidemiology and management costs associated with GW in Spain. METHODS A 1-year (2005) retrospective observational study was performed among a sample of gynaecologists, dermatologists and urologists in six autonomous regions in Spain. Men and women with newly diagnosed, recurrent or resistant GW were included. We estimated the incidence (new and recurrent cases) and prevalence (also including resistant cases) of GW. Healthcare resource use were collected and combined with unit costs to assess the mean cost of GW management per patient. These figures were extrapolated to the 14- to 64-year-old Spanish population to estimate the total cost of GW management from the Third Party Payer (TPP) and societal perspectives. RESULTS The overall annual incidence of GW was estimated at 160.4 cases per 100,000. Overall prevalence was calculated as 182.1 cases per 100,000, corresponding to 56 446 GW cases annually (14- to 64-year-old population). The mean management cost was 833 euros and 1056 euro per patient from the TPP and societal perspective, respectively. The overall annual cost was estimated at 47 million euros and 59.6 million euros, from the TPP and societal perspective, respectively. CONCLUSION This study provides a first overview of the burden of GW in Spain. A quadrivalent HPV vaccine that prevents HPV 6, 11, 16, 18 related diseases will have the potential to significantly decrease the socio-economic burden associated with GW in Spain.

The use of sentinel lymph nodes in gynaecological malignancies.

Purpose of review Lymphatic mapping and sentinel node biopsy represent one of the most revolutionary advances in oncological surgery in recent years. In this review, the current state of sentinel node detection in gynaecological cancers and its use in vulvar and cervical cancer are assessed. Recent findings Since the recent clinical application of sentinel node biopsy for melanomas and breast cancer, there has been extensive research on the implementation of this technique to most solid neoplasias. Studies on the feasibility of sentinel node biopsy in vulvar cancer have shown that the status of the sentinel node is an accurate predictor of the status of inguinal nodes. The clinical implementation of the procedure requires validation and is under investigation. In the last two years, several pilot studies on the feasibility of lymphatic mapping/sentinel node biopsy in cervical cancer have yielded promising results. There is minimal experience of its use in endometrial cancer. Detailed pathological study of a sentinel node biopsy with ultrastaging and immunohistochemical or polymerase chain reaction analyses can identify lymph node micrometastasis that conventional methods would identify as negative for metastatic disease. The best histopathological procedure for sentinel node biopsy, the clinical significance of micrometastases, and the appropriate management of such micrometastases are currently under investigation. Summary Sentinel node biopsy is one of the main research interests in gynaecological oncological surgery. At present there are not enough data to permit modification of current treatment protocols. Large and multi-institutional trials are required in order to define the implementation of sentinel node biopsy in clinical practice with the objective of achieving safer and more conservative surgery.

Prospective evaluation of squamous cell carcinoma and carcinoembryonic antigen as prognostic factors in patients with cervical cancer.

Carcinoembryonic antigen (CEA) and squamous cell carcinoma(SCC) serum levels were prospectively determined in 159 untreated patients diagnosed with carcinoma of the uterine cervix from 1991 to 2001. The histological analysis showed epidermoid cancer in 117 patients, adenocarcinoma in 26 patients, adenosquamous carcinoma in 12 patients and other histological types in the remaining 4 patients. Tumor marker sensitivity was related to the histological type with abnormal SCC (>2 ng/ml) in 51.3% of squamous tumors in contrast to the 7.1% found in other histologies. By contrast, CEA sensitivity was not related to histology with abnormal values (>5 ng/ml) in 25% of squamous tumors, 19% of adenocarcinomas, 33% of adenosquamous carcinomas and 25% of other histologies. CEA and SCC serum levels were clearly related to tumor stage, parametrial invasion, tumor size and nodal involvement. Elevated pretreatment CEA indicates parametrial invasion with a probability of 82%. Likewise, pretreatment CEA and SCC serum levels were of prognostic value, with a shorter disease-free survival and overall survival in patients with abnormal levels. All patients with adenocarcinomas and abnormal CEA had relapse during follow-up. Multivariate analysis indicated that parametrial invasion, age, tumor size and SCC were independent prognostic factors. In conclusion, CEA and SCC are useful tumor markers in carcinomas of the uterine cervix, with a clear relationship with well-known prognostic factors (parametrial invasion, nodal involvement), and are of prognostic value.

Is vascular and lymphatic space invasion a main prognostic factor in uterine neoplasms with a sarcomatous component? A retrospective study of prognostic factors of 60 patients stratified by stages

BACKGROUND Sarcomatous neoplasms of the uterine corpus are still a challenge in terms of obtaining prognostic factors and the most optimum complementary treatment to surgery. The most important prognostic factor is stage; relapses usually appear during the first 2 years, and most patients die within the first 3 years. We have performed a multivariate study of prognostic factors, stratifying patients by stage, to determine their impact on overall survival, disease-free survival, local relapse-free survival, and distant metastasis-free survival. Special emphasis has been given to vascular and lymphatic space invasion (VLSI). METHODS Sixty patients diagnosed with uterine neoplasms with a main sarcomatous component were treated at Hospital Clínic i Universitari of Barcelona between January 1975 and June 1999. Pathologic type: 32 carcinosarcomas, 14 leiomyosarcomas, 9 adenosarcomas, and 5 endometrial stromal sarcomas. TREATMENT 58/60 surgery, 35/60 postoperative radiotherapy, 2/60 exclusive chemotherapy, and 3/60 complementary chemotherapy. FIGO stages: 43 Stage I, 4 Stage II, 11 Stage III, and 2 Stage IV. Variables analyzed: age, stage, vascular and lymphatic space invasion, myometrial invasion, mitotic index, tumor size, unicentricity/multicentricity, necrosis, and radiotherapy. STATISTICS the S and Cox proportional risk models. The partial effect of each risk factor was calculated by hazard ratio (HR) with a confidence interval of 95%. RESULTS Early stages: Multivariate analysis showed that tumor size larger than 8 cm and VLSI had an impact on overall survival (HR = 4.01 and HR = 24.45, respectively). VLSI was present in 23% of the cases. Myometrial invasion greater than 50% had an impact on disease-free survival and local relapse-free survival (HR was 9.75 and 3.20, respectively). VLSI had an impact on distant metastasis-free survival (HR = 2.92). Advanced stages: VLSI was present in 89% of the cases. Only leiomyosarcoma type made the overall survival worse (HR = 10.54). CONCLUSIONS Vascular and lymphatic space invasion was a relevant prognostic factor in our series, with an impact on overall survival and distant metastasis-free survival in early stages. In advanced stages, VLSI had no impact on survival, but was present in 89% of cases. Myometrial invasion >50% had an impact on local relapse. Advanced stages had a more aggressive behavior, and there was a higher incidence of poor prognostic factors in these stages. Nevertheless, prospective studies are still needed on prognostic factors and on the best treatment option.

Epidemiology and costs of screening and management of precancerous lesions of the cervix in Spain.

Objective. Oncogenic human papillomaviruses (HPVs) are essential causes of cervical cancer. Screening prevents cancer by detecting precancerous lesions (cervical intraepithelial neoplasia, CIN). Our aim was to assess the annual number of Pap smears and CIN diagnoses in Spain and to estimate associated management costs. Materials and Methods. A 1-year retrospective cross-sectional study was conducted among 65 gynecologists from public primary health care centers in 6 autonomous regions in Spain. We documented the total number of Pap smears performed and the management of women with CIN. Data on health care resource use related to CIN management for 2 years after diagnosis were collected and combined with unit costs to assess the mean cost per patient. We extrapolated to the general female Spanish population to estimate the total cost of screening and CIN management from the third-party payers perspective. Results. In our study sample, 3.5% of routine Pap smears were abnormal. We estimated that 7.6 million Pap smears are performed annually in Spain, at a cost of Euros 622 million (US

Guía de cribado del cáncer de cuello de útero en España, 2014

987). Furthermore, 40,530 women are annually diagnosed with CIN 1, 26,243 with CIN 2, and 28,423 with CIN 3. The mean cost of CIN management per patient was Euros 1,115 for CIN 1, Euros 1,626 for CIN 2, and Euros 2,090 for CIN 3. The total cost of CIN management was estimated at Euros 147 million (US

Neoplasia vulvar intraepitelial (VIN)

233). Conclusions. This study shows that the costs of screening and management of CIN represent a heavy burden to the public health system in Spain.