Development of biological tools to assess the role of TMPRSS4 and identification of novel tumor types with high expression of this prometastatic protein.

Metastatic spread is responsible for the majority of cancer deaths and identification of metastasis-related therapeutic targets is compulsory. TMPRSS4 is a pro-metastatic druggable transmembrane type II serine protease whose expression has been associated with the development of several cancer types and poor prognosis. To study the role and expression of this protease in cancer, we have developed molecular tools (active recombinant proteins and a polyclonal antibody) that can be used for diagnostic purposes and for testing anti-TMPRSS4 drugs. In addition, we have evaluated TMPRSS4 protein expression in several cancer tissue microarrays (TMAs). Full length and truncated TMPRSS4 recombinant proteins maintained the catalytic activity in two different expression systems (baculovirus and E. coli). Sensitivity of the rabbit polyclonal antisera against TMPRSS4 (ING-pAb) outperformed the antibody most commonly used in clinical settings. Analysis by immunohistochemistry in the different TMAs identified a subset of adenocarcinomas, squamous carcinomas, large cell carcinomas and carcinoids of the lung, which may define aggressive tumors. In conclusion, our biological tools will help the characterization of TMPRSS4 activity and protein expression, as well as the evaluation of anti-TMRSS4 drugs. Future studies should determine the clinical value of assessing TMPRSS4 levels in different types of lung cancer.

Distribución de genotipos del virus del papiloma humano en una población de mujeres españolas no vacunadas con enfermedad de vulva y vagina / The distribution of human papillomavirus genotypes within a population of non-vaccinated Spanish women with vulvar and vaginal pathology

En este estudio se han analizado un total de 86 muestras procedentes de biopsias vulvares y vaginales obtenidas en el Hospital General Universitario Gregorio Marañón de Madrid, con objeto de determinar la distribución de los genotipos del virus del papiloma humano (VPH) y el nivel de coinfección. Las muestras comprenden 61 casos de lesiones benignas vulvares (VBL), 5 lesiones intraepiteliales vulvares variedad usual (u-VIN), 2 carcinomas vulvares de células escamosas (VSCC), 9 lesiones benignas vaginales (VaBL), 4 lesiones intraepiteliales vaginales grado I (VaIN), 4 lesiones vaginales intraepiteliales grado II/III (VaIN-II/III) y un carcinoma vaginal epidermoide (VaSCC). El genotipado fue realizado con amplificación por PCR e hibridación reversa dot blot. En el total de esta serie de lesiones se detectaron 33 genotipos distintos de HPV, entre los que se incluyen 10 asociados con un alto riesgo de carcinogénesis (VPH-AR), 2 asociados con un riesgo altamente probable de carcinogénesis (VPH-PAR) y 5 asociados con un bajo riesgo de carcinogénesis (VPH-BR). En 3 muestras se detectó un VPH de genotipo indeterminado (VPH-X). Los genotipos de HPV más frecuentemente encontrados fueron el VPH-6 (10,3%; IC 95%: 6,6-15,1%), el VPH-16 (8,5%; IC 95%: 5,2-13%) y el VPH-11 (7,6%; IC 95%: 4,5-11,9%). El VPH-18 solamente fue detectado en el 0,9% (IC 95%: 0,1-3,2%) del total de virus encontrados en todas las lesiones. La coinfección por distintos genotipos del VPH se halló en el 30,2% del total de las lesiones (AU)

Vulvar and vaginal specimens were studied in order to determine the distribution of human papillomavirus (HPV) genotypes and co-infection occurrence. This information will contribute to the knowledge of HPV genotype distributions and provide an estimate of the prevalence of different oncogenic HPV genotypes found in patients in Madrid (Spain). A total of 86 vulvar and vaginal biopsies from the Hospital General Universitario Gregorio Marañón of Madrid were studied. These included 61 specimens with vulvar benign lesions (VBL), 5 usual vulvar intraepithelial lesions (u-VIN), 2 vulvar squamous cell carcinoma (VSCC), 9 vaginal benign lesions (VaBL), 4 vaginal intraepithelial lesions grade I (VaIN-I), 4 vaginal intraepithelial lesions grade II/III (VaIN-II/III) and one vaginal squamous cell carcinoma (VaSCC). HPV genotyping was performed with PCR amplification and reverse dot blot hybridization. 33 different HPV genotypes were detected, including 10 HPVs associated with a high risk of carcinogenesis, 2 HPVs associated with a highly likely risk of carcinogenesis and 5 HPVs associated with a low-risk of carcinogenesis. In 3 specimens, an uncharacteristic HPV genotype was detected. The most frequent HPV genotypes found were HPV-6 (10.3%; 95% CI: 6.6-15.1%), HPV-16 (8.5%; 95% CI: 5.2-13%) and HPV-11 (7.6%; 95% CI: 4.5-11.9%). HPV-18 was only detected in 0.9% (95% CI: 0.1-3.2%) of the total viruses detected in all lesions. HPV co-infections were found in 30.2% of all types of lesions. Benign lesions predominate in the pathology of the vulva and vagina. Although the presence of LR-HPVs is dominate among the BLV, the HR-HPVs are present in a significant number of cases (AU)

Assessment of MAGE-A expression in resected non-small cell lung cancer in relation to clinicopathologic features and mutational status of EGFR and KRAS.

Non-small cell lung cancer (NSCLC) is a major public health problem, accounting for more cancer-related deaths than any other cancer. Both immunotherapy, based on the expression of tumor-specific antigens, and targeted therapy, based on the presence of oncogenic mutations, are under development for NSCLC. In this study, we analyzed the expression of MAGE-A, a cancer-testis antigen, in tumors from a cohort of patients with resected NSCLC with respect to their clinicopathologic characteristics and their mutational status for the EGFR and KRAS genes. We found MAGE-A expression by IHC in 43% of the tumors. MAGE-A expression was significantly more frequent in squamous tumors than in adenocarcinomas, did not correlate with disease stage, but was correlated significantly with high tumor grade and worse survival. EGFR and KRAS mutations were present in adenocarcinomas, but not in squamous tumors. Whereas the presence of EGFR mutations did not seem to affect survival, the presence of KRAS mutations was associated with early-stage disease and better survival. MAGE-A expression was absent from adenocarcinomas with KRAS mutations, but not significantly different in tumors with or without EGFR mutations. Together, the reported results provide guidance for the design of combination therapies in patients with NSCLC.

Human papillomavirus genotypes in human immunodeficiency virus-positive patients with anal pathology in Madrid, Spain.

BACKGROUND: We studied anal specimens to determine the distribution of human papillomavirus (HPV) genotypes and co-infection occurrence. This information will contribute to the knowledge of HPV genotype distributions and provide an estimate of the prevalence of different oncogenic HPV genotypes found in patients in Madrid (Spain). METHODS: We studied a total of 82 anal biopsies from the Hospital General Universitario Gregorio Marañón of Madrid. These included 4 specimens with benign lesions, 52 specimens with low-grade anal squamous intraepithelial lesion, 24 specimens with high-grade anal squamous intraepithelial lesions and 2 specimens with invasive anal carcinoma. HPV genotyping was performed with PCR amplification and reverse dot blot hybridization. RESULTS: We detected 33 different HPV genotypes, including 16 HPVs associated with a high risk of carcinogenesis, 3 HPVs associated with a highly likely risk of carcinogenesis and 14 HPVs associated with a low-risk of carcinogenesis. In two specimens, an uncharacterized HPV genotype was detected. The most frequent HPV genotypes found were HPV-16 (10.3%; 95% CI: 6.6%-15.1%), HPV-52 (8.5%; 95% CI: 5.2%-13%) and HPV-43/44 (7.6%; 95% CI: 4.5%-11.9%). HPV-18 was only detected in 0.9% (95% CI: 0.1%-3.2%) of the total viruses detected in all lesions. HPV co-infections were found in 83.9% of all types of lesions. The majority of cases (90.2%) were concomitantly infected with the human immunodeficiency virus (HIV). CONCLUSION: The prevalence of high-risk carcinogenic genotypes in anal pathological samples was remarkable. Therefore, further studies that include a greater number of samples, particularly invasive carcinoma cases are needed to evaluate the potential influence of these HPV genotypes in the appearance of anal carcinomas. Also, the influence of other accompanying infections should be evaluated clarify the appearance of this type of carcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2075238024106058.

Genotype distribution of human papillomavirus (HPV) in histological sections of cervical intraepithelial neoplasia and invasive cervical carcinoma in Madrid, Spain.

BACKGROUND: Human Papillomavirus (HPV) genotype distribution and co-infection occurrence was studied in cervical specimens from the city of Madrid (Spain), as a contribution to the knowledge of Human Papillomavirus genotype distribution and prevalence of carcinogenic HPV types in cervical lesions in Spain. METHODS: A total of 533 abnormal specimens, from the Hospital General Universitario "Gregorio Marañón" of Madrid, were studied. These included 19 benign lesions, 349 cervical intraepithelial neoplasias 1 (CIN1), 158 CIN2-3 and 7 invasive cervical carcinomas (ICC). HPV genotyping was performed using PCR and tube array hybridization. RESULTS: We detected 20 different HPV types: 13 carcinogenic high-risk HPV types (HR-HPVs), 2 probably carcinogenic high-risk HPV types (PHR-HPVs) and 5 carcinogenic low-risk HPV types (LR-HPVs). The most frequent HPV genotypes found in all specimens were HPV16 (26.0%), 31 (10.7%) and 58 (8.0%). HPV 18 was only detected in 5.0%. Co-infections were found in 30.7% of CIN 1 and 18.4% cases of CIN2-3. The highest percentage of HR HPVs was found in those specimens with a CIN2-3 lesion (93.7%). CONCLUSION: As our study shows the current tetravalent vaccine could be effective in our geographical area for preventing all the invasive cervical carcinomas. In addition, upon the estimates of the important presence of other HR-HPV types - such as 31, 58, 33 and 52 - in different preneoplasic lesions the effectiveness of HPV vaccination in our geographical area, and others with similar genotype distribution, should be limited.

Differences in the expression of five senescence markers in oral cancer, oral leukoplakia and control samples in humans.

Oncogene-induced senescence (OIS) may be a response to oncogenic activation, acting as a natural barrier against carcinogenesis at a premalignant stage. Thus, numerous cells in premalignant lesions enter senescence, but none or few in malignant tumours. This event could be due to the loss of senescence pathway effectors, including p16 (INK4a)-pRb or ARF-p53. The aim of this study was to characterize and compare the expression of certain senescent markers between oral precancer and cancer tissue samples. The expression of cyclin D1, Rb, maspin, p53 and mouse double minute 2 (MDM2) was analyzed in 20 paraffin-embedded tissue samples of normal oral mucosa (NOM), 14 samples of oral leukoplakia without dysplasia (OLD-), 11 samples of leukoplakia with dysplasia (OLD+) and 15 samples of oral squamous cell carcinoma (OSCC) by immunohistochemistry in tissue arrays. The expression of p16-pRb pathway markers, cyclin D1, maspin and Rb, was more frequent in OLD+ samples than in OSCC samples, although a statistical significance was only observed for maspin (P=0.036). Cyclin D1 expression was also significantly more frequent in OLD- samples vs. NOM samples. For the ARF-p53 pathway, the expression of p53 and MDM2 was significantly more frequent in the OLD- samples compared to in the NOM ones. These findings may indicate a role for cellular senescence in oral carcinogenesis, considering maspin as a reliable senescence marker and prognostic factor in oral premalignant lesions.

New perspectives on the dynamic behaviour of oral lichen planus.

Lichen planus, a chronic inflammatory disease that affects the skin and mucous membranes, is one of the most frequent dermatological disorders of the oral cavity. The prevalence of oral lichen planus ranges from 0.2% to 4%. The triggering factors remain unknown. Oral lichen planus can be considered to be a chronic disease of long duration with a dynamic evolution and frequent changes in clinical appearance. Three successive active stages can be distinguished, without sharp limits between them: an initial stage; a protracted intermediate stage with alternate periods of variable activity and quiescence, which carries a progressively increasing risk of malignant transformation; and a late stage that often ends in a clinically little-known, inactive cicatricial post-lichen stage, which does not respond to steroid treatment but retains the same risk.

Influencia pronóstica de la pérdida de la expresión del antígeno del grupo sanguíneo A en el carcinoma no microcítico de pulmón en estadio I patológico / Prognostic Influence of Loss of Blood Group A Antigen Expression in Pathologic Stage I Non-Small-Cell Lung Cancer

Introducción: En la literatura científica se han publicado resultados contradictorios sobre el valor pronóstico de la pérdida de la expresión del antígeno de grupo sanguíneo A (GSA) en el cáncer de pulmón, por lo que analizamos retrospectivamente este hecho en nuestra serie quirúrgica. Pacientes y métodos. En un estudio multicéntrico de 402 pacientes con carcinoma no microcítico de pulmón (CNMP) en estadio I patológico según la nueva clasificación TNM-2009 se analizó la influencia pronóstica de la pérdida de la expresión del antígeno del GSA en los 209 pacientes con grupos sanguíneos A o AB. Resultados: La supervivencia a los 5 años de los pacientes en estadio I patológico que mantenían la expresión del antígeno del GSA fue del 73%, frente a una supervivencia del 53% en los pacientes que habían perdido la expresión del mismo (p=0,03). Cuando se analizó la supervivencia subdividiendo la muestra en estadios IA y IB, solo se alcanzó la significación estadística en el estadio IA (p=0,038). Al analizar la supervivencia según el tipo histológico, los pacientes con adenocarcinoma que perdían la expresión del antígeno del GSA tenían una menor supervivencia, con una p estadísticamente muy significativa (p=0,003). El análisis multivariable mostró que la edad, el género y la expresión del antígeno del GSA eran factores pronósticos independientes. Conclusiones: La pérdida de la expresión del antígeno del grupo sanguíneo A tiene una influencia pronóstica negativa en el CNMP estadio I patológico, sobre todo en el tipo histológico adenocarcinoma(AU)

Introduction: In the scientific literature, contradictory results has been published on the prognostic value of the loss of expression of blood group antigen A (BAA) in lung cancer. The objective of our study was to analyze this fact in our surgical series. Patients and methods: In a multicenter study, 402 non-small-cell lung cancer (NSCLC) patients were included. All were classified as stage-I according to the last 2009-TNM classification. We analyzed the prognostic influence of the loss of expression of BAA in the 209 patients expressing blood group A or AB. Results: The 5-year cumulative survival was 73% for patients expressing BAA vs 53% for patients with loss of expression (P=.03). When patients were grouped into stages IA and IB, statistical significance was only observed in stage I-A (P=.038). When we analyzed the survival according to histologic type, those patients with adenocarcinoma and loss of expression of BAA had a lower survival rate that was statistically very significant (P=.003). The multivariate analysis showed that age, gender and expression of BAA were independent prognostic factors. Conclusions: The loss of expression of blood group antigen A has a negative prognostic impact in stage I NSCLC, especially in patients with adenocarcinoma(AU)

Prognostic influence of loss of blood group A antigen expression in pathologic stage I non-small-cell lung cancer.

INTRODUCTION: In the scientific literature, contradictory results has been published on the prognostic value of the loss of expression of blood group antigen A (BAA) in lung cancer. The objective of our study was to analyze this fact in our surgical series. PATIENTS AND METHODS: In a multicenter study, 402 non-small-cell lung cancer (NSCLC) patients were included. All were classified as stage-I according to the last 2009-TNM classification. We analyzed the prognostic influence of the loss of expression of BAA in the 209 patients expressing blood group A or AB. RESULTS: The 5-year cumulative survival was 73% for patients expressing BAA vs 53% for patients with loss of expression (P=.03). When patients were grouped into stages IA and IB, statistical significance was only observed in stage I-A (P=.038). When we analyzed the survival according to histologic type, those patients with adenocarcinoma and loss of expression of BAA had a lower survival rate that was statistically very significant (P=.003). The multivariate analysis showed that age, gender and expression of BAA were independent prognostic factors. CONCLUSIONS: The loss of expression of blood group antigen A has a negative prognostic impact in stage I NSCLC, especially in patients with adenocarcinoma.

Prognostic influence of the third Gleason grade in prostatectomy specimens.

BACKGROUND: Gleason grading of prostatic specimens remains as one of the most powerful factors predicting prognosis in patients with prostate cancer. This grading system was created by Donald Gleason about 49 years ago and it takes into account the 2 most prevalent grades in the tumor sample, but it does not consider the presence of a third high grade pattern when it represents less than 5% of the whole radical prostatectomy specimen. OBJECTIVE: The objective of the present study is to determine whether the existence of a third pattern of growth in the radical prostatectomy samples correlates with a shorter recurrence free survival. MATERIAL AND METHODS: We have reviewed 85 consecutive specimens of radical prostatectomy from patients with clinical localized disease. Those who received previous hormonal or radiation therapy were excluded. We have determined the Gleason grade and also the presence of a third higher grade pattern, surgical margins status, capsular, vascular, and lymphatic invasion. We have analyzed whether the existence of this high grade third pattern areas influences prognosis. Recurrence was defined with PSA levels (biochemical recurrence). RESULTS: We have shown that the presence of a Gleason's grade 5 pattern of growth worsens prognosis in patients with tumors grade 7 (both 3 + 4 and 4 + 3), with a shorter time to recurrence. The latter group of patients behaves more like patients with Gleason 8 tumors. This worse prognosis should be taken into account for patient surveillance and future adjuvant therapies. We feel this information is relevant and should be reported in the pathology reports.

Mutaciones en los genes HFE y TFR2 en un paciente español con hemocromatosis / Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis

La enfermedad por sobrecarga de hierro está originada por diversas anomalías genéticas. El estudio genético de esta enfermedad confirma su carácter hereditario y nos permite ofrecer consejo genético a los familiares en primer grado. Hemos realizado resonancia magnética y biopsia de hígado en un paciente asintomático con más de 1.000 mg/l de ferritina en suero, y hemos analizado los genes implicados en el metabolismo del hierro. El fenotipo de sobrecarga de hierro se confirmó por la presencia de un patrón de depósito de hierro en el hígado con predominio periportal que sugiere la existencia de una enfermedad genética. En el caso que presentamos, el estudio genético reveló que el paciente es doble heterocigoto para las mutaciones c.187C>G (p.H63D) y c.840C>G (p.F280L) en los genes HFE y receptor 2 de transferrina (TFR2), respectivamente(AU)

Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 mg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D) and c.840C>G (p.F280L) in the HFE and transferrin receptor 2 (TFR2) genes, respectively(AU)

Lung carcinoma with rhabdoid component. A series of seven cases associated with uncommon types of non-small cell lung carcinomas and alveolar entrapment.

Rhabdoid tumor, included in the WHO classification among large cell carcinomas of the lung, is an uncommon type of lung carcinoma with poor prognosis. We report a series of 7 cases of lung carcinomas with rhabdoid component in 10% and 80% of the tumor. The associated tumor was adenocarcinoma in 3 cases--one of them with focal micropapillary pattern--large cell carcinoma in 2 cases, squamous cell carcinoma in 1 case and pleomorphic carcinoma in 1 case. Two adenocarcinomas showed a focal spindle cell component. Micropapillary and pleomorphic types had not been reported before as a component associated with rhabdoid carcinomas. All cases were positive for vimentin, and AE1/AE3 cytokeratin and 5 cases for cytokeratin 7. All cases were negative for muscle and endothelial markers and for chromogranin A. Synaptophysin was focally positive only in one case. Alveolar trapping inside the tumor was present in 3 cases--a phenomenon not well studied in lung carcinomas and also not reported in tumors with rhabdoid component. Five patients died because of the tumor within 2 to 31 months after diagnosis, one of myocardial infarction and only one is alive and disease free 123 months after the diagnosis. In summary, we describe 7 new cases of this uncommon lung tumor with aggressive clinical course, associated with infrequent histological types in nonrhabdoid component and with alveolar trapping, a nondescribed finding.

Sildenafil as a protecting drug for warm ischemic kidney transplants: experimental results.

PURPOSE: In an experimental model we studied the protective effects of the phosphodiesterase-5 inhibitor sildenafil on kidney grafts autotransplanted after 45 minutes of warm ischemia by vascular clamping, nephrectomy and 60 minutes of isolated hypothermic pump perfusion. MATERIALS AND METHODS: A total of 14 laboratory minipigs were divided into group 1-7 administered 100 mg sildenafil orally 1.5 hours preoperatively and group 2-7 in which no sildenafil was given. Right single nephrectomy was completed after 45 minutes of warm ischemia by complete vascular clamping. Before autotransplantation all kidneys underwent 60 minutes of hypothermic pulsatile perfusion. Renal flow, arterial pressure and renal vascular resistance were recorded in real time for 60 minutes after autotransplantation. Nitric oxide levels were determined in blood samples from the renal vein at predefined intervals. Optical and electronic microscopy was done in all organs at the end of the procedure. RESULTS: In group 1 vs 2 renal vascular flow was significantly higher (155.30 vs 29.04 ml per minute per 100 gm) and renal vascular resistance was significantly lower (0.59 vs 3.10 mm Hg/ml per minute, each p <0.01). No significant differences were observed in systemic arterial pressure between groups 1 and 2 (84.08 and 84.65 mm Hg, respectively, p >0.05). Nitric oxide levels were significantly higher for all periods in group 1 (49.94 vs 16.85 muM, p <0.01). No significant differences were observed in histological studies, although endothelial cell structure was better preserved in the sildenafil group. CONCLUSIONS: To our knowledge our study suggests for the first time in the literature a positive effect of sildenafil in the immediate posttransplantation outcome of warm ischemic kidneys without secondary systemic effects.

Metástasis retroperitoneal de liposarcoma mixoide/células redondas: patrón metastásico peculiar / Retroperitoneal metastases of myxoid/round cell liposarcoma: a peculiar metastatic pattern

El liposarcoma mixoide aparece en extremidades depacientes jóvenes, y muestra una apariencia mixoide, y unascaracterísticas citogenéticas determinantes.Presentamos el caso de un varón de 37 años con un grantumor retroperitoneal, que había sido diagnosticado previamentede un tumor de muslo. El tumor se caracterizaba porpresentar una red vascular capilar plexiforme con célulasfusiformes monomorfas y células redondas atípicas. Mostrabauna translocación (12;16). Planteó el diagnostico diferencialcon liposarcoma desdiferenciado con áreas de tipomixofibrosarcoma.El liposarcoma mixoide en retroperitoneo es más probablede origen secundario, por la peculiar propensión del LPSmixoide de extremidad a dar metástasis en tejidos blandosextrapulmonares, sobre todo retroperitoneo (AU)

Myxoid liposarcoma usually ocurs in extremities inyounger patients, showing a myxoid appearance and distinctivecytogenetic features.We report a huge retroperitoneal myxoid tumor, with ina patient that initially presented a liposarcoma of the thigh.The tumour showed a fine plexiform capillary network withmonomorphic spindle-cell and atypical round cells. FISHshowed a translocation t(12;16). This retroperitonealmyxoid tumor may be confused with dedifferentiated liposarcomawith myxofibrosarcoma-like areas.The retroperitoneal myxoid liposarcoma is more likelyto be secondary. Retroperitoneum is the most common siteof extrapulmonary metastatic myxoid liposarcoma (AU)

Losses of expression of the antigens A, Lea and Lex and over-expression of Ley in carcinomas and HG-SIL of the uterine cervix.

BACKGROUND: The glycosylation of a great number of molecules, glyco-protein or glycolipids, has been of interest for decades. OBJECTIVE: To compare the expressive patterns of the isoantigenic determinants of histo-blood groups ABH and Lewis in squamous and simple epithelium and in precursors and cancers of the cervix. METHODS: A total of 36 lesions and neoplasms (10 LG-SIL, 16 HG-SIL and 10 invasive carcinomas) have been studied with immunohistochemical techniques, using monoclonal antibodies (MoAb BG1 to BG8) for precursor chains, blood-group ABH and Lewis group Le(a), Le(b), Le(x), and Le(y), and four types of lectins. In addition, we have studied the expression of p53 protein and PCNA, establishing the rate of proliferation of each lesion. Using PCR techniques, we have also detected part of the intron of the E6 gene of HPV-16. RESULTS: In the invasive cervical carcinomas, we observed a loss of expression of the Le(x) antigen (p < 0.01). With regard to the progression of the different lesions studied, we found alterations in the patterns of expression of the antigens of the ABH and Lewis blood groups. There was a tendency towards a loss of expression and heterogeneous patterns in the more advanced lesions, as well as over-expression of the Le(y) antigens. With PCNA, we established a proliferative rate which tended to be greater in relation to the progression of the cervix neoplasms. CONCLUSION: These results indicate that there is a relation between the losses of histo-blood groups and the progression of the squamous intraepithelial lesions.

[Prognostic value of ERBB2 amplification and protein expression in small cell lung cancer]. / Valor pronóstico de la expresión y amplificación genética de c-erbB-2 en el carcinoma microcítico de pulmón.

OBJECTIVE: Our objective was to evaluate ERBB2 oncogene amplification using fluorescence in situ hybridization (FISH) and protein overexpression using immunohistochemical techniques, and to explore their possible prognostic value in a series of patients with small cell carcinoma. PATIENTS AND METHODS: Included in the study were 99 patients with small cell tumors, classified in 2 broad groups: patients with limited locally advanced disease and patients with disseminated disease. Material for study was obtained in 97% of the cases (96/99) by means of endoscopic biopsy and by tomography-guided needle biopsy in the remaining 3% (3/99). Survival was analyzed using the Kaplan-Meier method. RESULTS: The 92 men (92.9%) and 7 women (7.1%) in the study had a mean (SD) age of 62.9 (10.4) years (range, 36-81 years); 39.4% (n=39) and 60.6% (n=60) of the subjects had limited and disseminated disease, respectively. ERBB2 protein overexpression was observed in 26.3% of the patients (n=26), 15.4% (n=4) of whom had limited disease and 84.6% (n=22) of whom had disseminated disease (P=.005). Although mean survival was slightly longer for patients who were negative for ERBB2 protein overexpression, the difference was not statistically significant. FISH identified gene amplification in 6.3% (1 in 16) of the studied cases (ratio, 2.3). CONCLUSIONS: The protein product of the ERBB2 oncogene is overexpressed in 33.3% of small cell lung carcinomas and is associated with the presence of disseminated disease. Further studies are necessary to evaluate the possible benefits of specific treatment.

Valor pronóstico de la expresión y amplificación genética de c-erbB-2 en el carcinoma microcítico de pulmón / Prognostic value of ERBB2 amplification and protein expression in small cell lung cancer

Objetivo: El propósito de nuestro estudio ha sido evaluar la sobreexpresión proteica de c-erbB-2 mediante técnicas de inmunohistoquímica y la amplificación del oncogén mediante hibridación in situ fluorescente, en una serie de carcinomas microcíticos, correlacionándola con las posibles implicaciones pronósticas. Pacientes y métodos: Se incluyó a 99 pacientes con tumores microcíticos clasificados en 2 grandes grupos: enfermedad limitada o localmente avanzada y enfermedad diseminada. El material para estudio se obtuvo mediante biopsia endoscópica en el 97% de los casos (96/99) o mediante punción guiada por tomografía computarizada en el 3% restante (3/99). La supervivencia se analizó con el método de Kaplan-Meier. Resultados: La media de edad ± desviación estándar de los pacientes fue de 62,9 ± 10,4 años (rango: 36-81). El 92,9% (n = 92) eran varones y el 7,1% mujeres (n = 7). Un 39,4% (n = 39) presentaba enfermedad limitada y el 60,6% (n = 60) enfermedad diseminada. La sobreexpresión proteica de c-erbB-2 se observó en el 26,3% de los casos (n = 26), de los cuales un 15,4% (n = 4) presentaba enfermedad limitada y el 84,6% restante (n = 22) enfermedad diseminada (p = 0,005). La media de supervivencia fue ligeramente mayor para los pacientes con c-erbB-2 negativo que en aquéllos con c-erbB-2 positivo, pero esta diferencia no fue estadísticamente significativa. La técnica de hibridación in situ fluorescente mostró amplificación génica en el 6,3% (1/16) de los casos estudiados, con un índice de 2,3. Conclusiones: El producto proteico del oncogén c-erbB-2 se sobreexpresa en un 33,3% de los carcinomas microcíticos pulmonares y se asocia a la presencia de enfermedad diseminada. Son necesarios nuevos estudios para evaluar el posible beneficio del tratamiento específico

Objective: Our objective was to evaluate ERBB2 oncogene amplification using fluorescence in situ hybridization (FISH) and protein overexpression using immunohistochemical techniques, and to explore their possible prognostic value in a series of patients with small cell carcinoma. Patients and methods: Included in the study were 99 patients with small cell tumors, classified in 2 broad groups: patients with limited locally advanced disease and patients with disseminated disease. Material for study was obtained in 97% of the cases (96/99) by means of endoscopic biopsy and by tomography-guided needle biopsy in the remaining 3% (3/99). Survival was analyzed using the Kaplan-Meier method. Results: The 92 men (92.9%) and 7 women (7.1%) in the study had a mean (SD) age of 62.9 (10.4) years (range, 36-81 years); 39.4% (n=39) and 60.6% (n=60) of the subjects had limited and disseminated disease, respectively. ERBB2 protein overexpression was observed in 26.3% of the patients (n=26), 15.4% (n=4) of whom had limited disease and 84.6% (n=22) of whom had disseminated disease (P=.005). Although mean survival was slightly longer for patients who were negative for ERBB2 protein overexpression, the difference was not statistically significant. FISH identified gene amplification in 6.3% (1 in 16) of the studied cases (ratio, 2.3). Conclusions: The protein product of the ERBB2 oncogene is overexpressed in 33.3% of small cell lung carcinomas and is associated with the presence of disseminated disease. Further studies are necessary to evaluate the possible benefits of specific treatment

Micropapillary lung adenocarcinoma: a distinctive histologic subtype with prognostic significance. Case series.

The aims of the present work were to evaluate the prognostic significance of the micropapillary pattern of lung adenocarcinoma and determine whether there are differences in the behavior of this type of tumor according to its immunohistochemical profile. A series of 191 consecutively resected pulmonary adenocarcinomas were divided into those with (n = 62) and those without (n = 129) micropapillary components. The disease was stage I in 38 and 54 patients, respectively. The 5-year survival rates of patients with and without micropapillary components were 54% and 77%, respectively (log rank P = .03). In multivariate survival analysis, the micropapillary component proved to be an independent prognostic factor (hazard ratio, 3.2). Five autopsy cases were used to investigate the immunohistochemical profile. The percentages of cases positive for various markers were 56.7 for p53, 94 for Ki67, 85.1 for c-myc, 2.9 for Bcl-2, 35.8 for epidermal growth factor receptor, 43.3 for cyclin D1, and 46.3 for Bax. The prognostic value was evaluated according to the expression of the different markers in micropapillary carcinomas in stage I. In univariate analysis, only cyclin D1 expression and Bax expression were associated with significantly worse survival (log rank P = .03 and P = .02, respectively). We conclude that it is important to recognize the micropapillary growth pattern in lung adenocarcinoma. Moreover, cyclin D1 and Bax seem to be markers of a poor prognosis.

Large cell and small cell neuroendocrine bladder carcinoma: immunohistochemical and outcome study in a single institution.

We studied 44 cases of small cell bladder carcinoma (SCBC) and 2 cases of large cell neuroendocrine bladder carcinoma (LCNBC) to determine the immunohistochemical profile and biologic behavior. Thyroid transcription factor (TTF)-1, cytokeratin (CK)20, chromogranin A (CgA), synaptophysin, neuron-specific enolase (NSE), and Leu-7 studies were performed. TTF-1+ cases were stained for surfactant protein A (SP-A). The immunohistochemical profile for 44 SCBC cases was as follows: TTF-1+, 11 (25%); CK20+, 3 (7%); CgA+, 13 (30%); synaptophysin+, 22 (50%); NSE+, 35 (80%); and Leu-7+, 30 (68%), and for 2 LCNBC cases was as follows: TTF-1+, 2 (100%); CgA+, (50%); synaptophysin+, 1 (50%); NSE+, 2 (100%); and Leu- 7+, 2 (100%). All cases with TTF-1 expression were negative for SP-A, except 1 case. This case was a mixed SCBC with TTF-1 expression in the urothelial component, which also expressed SP-A. Immunohistochemical markers were not associated with survival. The prognosis of SCBC is relatively better than its pulmonary counterpart. LCNBC seems to be a rarely recognized entity. TTF-1 expression is not limited to small cell lung carcinoma.

The side of pneumonectomy influences long-term survival in stage I and II non-small cell lung cancer.

BACKGROUND: The impact of pneumonectomy as an independent factor on long-term survival after lung resection for centrally or locally advanced non-small cell lung cancer (NSCLC) remains controversial. The aim of this paper is to study the impact of pneumonectomy, and the influence of side of surgery, on long-term survival in patients with pathologic stage I and II NSCLC. METHODS: A retrospective review of a prospective multi-institutional database of patients operated on for lung cancer was undertaken. In all, 1,475 patients with pathologic stage I or II NSCLC were studied (421 underwent pneumonectomy; 1,054 had a lobectomy/bilobectomy). Survival and impact of side of surgery for pneumonectomy and lesser resection groups were analyzed and compared using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Median survival was worse after pneumonectomy than after less extensive resections for patients overall (33 versus 57 months) and for those with stage I NSCLC (38 versus 70 months); however, median survival was better after pneumonectomy for stage II left tumors (55 versus 19 months). Pneumonectomy was an independent adverse determinant of survival for both stage I right tumors (p < 0.001) and stage I left tumors (p < 0.001), but was associated with improved survival for stage II left tumors (p = 0.009). CONCLUSIONS: Pneumonectomy was found to be an independent determinant of survival in patients with stage I and II NSCLC, but results differed for right- and left-sided tumors. Further studies of survival comparing pneumonectomy with lesser resections should differentiate between right and left procedures.