Unlocking Overexpressed Membrane Proteins to Guide Breast Cancer Precision Medicine.

Breast cancer (BC) is a prevalent form of cancer affecting women worldwide. However, the effectiveness of current BC drugs is limited by issues such as systemic toxicity, drug resistance, and severe side effects. Consequently, there is an urgent need for new therapeutic targets and improved tumor tracking methods. This study aims to address these challenges by proposing a strategy for identifying membrane proteins in tumors that can be targeted for specific BC therapy and diagnosis. The strategy involves the analyses of gene expressions in breast tumor and non-tumor tissues and other healthy tissues by using comprehensive bioinformatics analysis from The Cancer Genome Atlas (TCGA), UALCAN, TNM Plot, and LinkedOmics. By employing this strategy, we identified four transcripts (LRRC15, EFNA3, TSPAN13, and CA12) that encoded membrane proteins with an increased expression in BC tissue compared to healthy tissue. These four transcripts also demonstrated high accuracy, specificity, and accuracy in identifying tumor samples, as confirmed by the ROC curve. Additionally, tissue microarray (TMA) analysis revealed increased expressions of the four proteins in tumor tissues across all molecular subtypes compared to the adjacent breast tissue. Moreover, the analysis of human interactome data demonstrated the important roles of these proteins in various cancer-related pathways. Taken together, these findings suggest that LRRC15, EFNA3, TSPAN13, and CA12 can serve as potential biomarkers for improving cancer diagnosis screening and as suitable targets for therapy with reduced side effects and enhanced efficacy.

Exploring Real-World HER2-Low Data in Early-Stage Triple-Negative Breast Cancer: Insights and Implications.

Purpose: This study aimed to compare the clinical behavior, clinicopathological and sociodemographic characteristics of patients with early-stage triple-negative breast cancer (TNBC) who belong to the HER2-low and HER2-zero subgroups. Patients and Methods: This study involved a thorough search in the internal database of a single Brazilian institution to identify women with TNBC who underwent neoadjuvant chemotherapy (NACT) followed by curative surgery within the period from January 2010 to December 2014. HER2 analysis through immunohistochemistry (IHC) and, if required, amplification by in situ hybridization, was conducted using core biopsy samples. The study assesses outcomes of residual cancer burden (RCB), event-free survival (EFS), and overall survival (OS). Results: A total of 170 cases were analyzed, with a mean age of 51.4 years (standard deviation, SD 11.2). The HER2 status was categorized as IHC 0, 1+, or 2+ in 80 (47.1%), 73 (42.9%), and 17 (10%) patients, respectively. No significant differences were observed in the prevalence of clinical pathological characteristics among the subgroups. The absence of significant results for clinicopathological and demographic features hindered the multivariate analysis of HER2 subgroups. Similarly, no significant differences were found in the RCB, EFS, and OS outcomes between HER2 subgroups. Conclusion: The findings of this study suggest that, in early-stage TNBC, the clinical behavior and survival outcomes of the HER2-low subgroup may not differ significantly from those of the HER2-zero subgroup.

Exploring biomarkers and prognostic factors in uterine carcinosarcoma: An insight into L1CAM, CDX2, p53, and MSI status.

BACKGROUND: Uterine Carcinosarcomas (UCS) are a rare type of cancer composed of an admixture of high-grade carcinomatous and sarcomatous elements. Clinicopathological prognostic factors in UCS are well established, but studies that approach the impact of biomarkers in this unusual disease are scarce. The study objective was to evaluate the prevalence and prognostic impact of a panel of prominent biomarkers in uterine carcinosarcoma (UCS) using an immunohistochemical characterization with four biomarkers. METHODS AND FINDINGS: The internal database of a single Brazilian institution was carefully explored to select women diagnosed with UCS who were submitted to surgery and postoperative chemotherapy with carboplatin and paclitaxel between January 2012 and December 2017. Tissue microarrays containing UCS samples were evaluated by immunohistochemistry for L1CAM, CDX2, p53 and microsatellite instability markers. A total of 57 cases were included. The mean age was 65.3 years (standard deviation, SD 7.0). L1CAM was negative (score 0, no staining) in 27 (47.4%) patients. Of L1CAM-positive, 10 (17.5%) showed weak (score 1, <10%), 6 (10.5%) showed moderate (score 2, between 10-50%), and 14 (24.6%) showed strong L1CAM staining (score 3, ≧50%). dMMR occurred in 3 (5.3%) cases. The p53 was aberrantly expressed in 15 (26.3%) tumors. CDX2 was positive in 3 (5.3%) patients. The three-year progression-free survival (PFS) rate in the general population of the study was 21.2% (95% CI: 11.7-38.1) and the three-year overall survival (OS) rate was 29.4% (95% CI: 18.1-47.6). By multivariate analysis, the presence of metastases and CDX2-positive were significantly associated with poorer PFS (p < 0.001 and p = 0.002, respectively) and OS (p < 0.001 and p = 0.009, respectively). CONCLUSION: The strong influence of CDX2 on prognosis requires further investigation. Biological or molecular variability may have impaired the assessment of the impact of the other markers on survival.

Association of Swede Score and 2011 IFCPC Nomenclature in Women with Abnormal Cytology.

OBJECTIVE: To assess the association between two colposcopic indices, the Swede score and the 2011 International Federation of Cervical Pathology and Colposcopy (IFCPC) Nomenclature as well as to determine the efficacy of the Swede score with cutoffs of 7 and 8. METHODS: In the present cross-sectional pilot study, 34 women who had at least 1 colposcopy-directed biopsy due to abnormal cytology were enrolled. The colposcopic findings were scored by both the Swede score and the 2011 IFCPC Nomenclature and were compared with each other. The Kappa coefficient and the McNemar test were used. Accuracy, sensitivity, specificity, and positive and negative predictive values (NPV and PPV, respectively) were calculated, as well as the effectiveness with cutoffs of 7 and 8 in identifying cervical intraepithelial neoplasm (CIN) 2+ when using the Swede score. RESULTS: The correlation between the 2 colposcopic indices was 79.41%. The Kappa coefficient and the McNemar p-value were 0.55 and 0.37, respectively. The IFCPC Nomenclature had sensitivity, specificity, accuracy, PPV, and NPV of 85.71, 55.00, 67.64, 57.14, and 84.61%, respectively. The Swede score had sensitivity, specificity, accuracy, PPV, and NPV of 100, 63.15, 79.41, 68.18, and 100%, respectively. A Swede score cutoff of 7 for CIN 2+ detection had a specificity of 94.73%, while with a cutoff of 8 it increased to 100%. The sensitivity for both values was 60%. The PPV and NPV for cutoffs of 7 and 8 were 90 and 75 and 100 and 76%, respectively. CONCLUSION: Although both colposcopic indices have good reproducibility, the Swede score showed greater accuracy, sensitivity, and specificity in identifying CIN 2 + , especially when using a cutoff of 8.

OBJETIVO: Avaliar a associação entre dois índices colposcópicos, o escore Swede e a Nomenclatura International Federation of Cervical Pathology and Colposcopy (IFCPC, na sigla em inglês) 2011, assim como determinar a eficácia do escore Swede com os pontos de corte 7 e 8. MéTODOS: Trata-se de um estudo transversal, com 34 mulheres incluídas, que realizaram colposcopia com biópsia dirigida devido a uma citologia anormal. Os achados colposcópicos foram categorizados pelo escore Swede e pela Nomenclatura IFCPC 2011 e comparados um com o outro. Foram avaliados o coeficiente Kappa e o teste de McNemar e foram calculados a acurácia, a sensibilidade, a especificidade e valores preditivos negativos e positivos (VPN e VPP, respectivamente) de cada índice, assim como a eficácia com os pontos de corte 7 e 8 do escore Swede para determinar as lesões de neoplasia intraepitelial cervical (NIC) 2 + . RESULTADOS: A concordância entre os 2 índices foi de 79,41% e o coeficiente Kappa e o valor-p do teste de McNemar foram 0.55 e 0.37, respectivamente. Pela Nomenclatura IFCPC 2011, obtivemos como sensibilidade, especificidade, acurácia, VPP e VPN, respectivamente: 85,71, 55,00, 67,64, 57,14 e 84,61%. Pelo escore Swede obtivemos como sensibilidade, especificidade, acurácia, VPP e VPN, respectivamente: 100, 63,15, 79,41, 68,18 e 100%. O uso do escore Swede para detecção das lesões NIC 2+ obteve como especificidade 94,73% com o valor de corte de 7, enquanto o valor de corte 8 obteve 100%. A sensibilidade para ambos os cortes foi de 60%. O VPP e o VPN com os cortes 7 e 8 foram, respectivamente: 90,00 e 75,00 e 100,00 e 76,00%. CONCLUSãO: Ambos os índices colposcópicos tiveram boa reprodutibilidade; no entanto, o escore Swede mostrou melhor acurácia, sensibilidade e especificidade em identificar as lesões NIC 2+ e o melhor ponto de corte para identificar as lesões NIC2+ foi com o valor 8.

Association of Swede Score and 2011 IFCPC Nomenclature in Women with Abnormal Cytology / A Associação entre o escore Swede e a nomenclatura IFCPC 2011 em mulheres com citologia anormal

Abstract Objective To assess the association between two colposcopic indices, the Swede score and the 2011 International Federation of Cervical Pathology and Colposcopy (IFCPC) Nomenclature as well as to determine the efficacy of the Swede score with cutoffs of 7 and 8. Methods In the present cross-sectional pilot study, 34 women who had at least 1 colposcopy-directed biopsy due to abnormal cytology were enrolled. The colposcopic findings were scored by both the Swede score and the 2011 IFCPC Nomenclature and were compared with each other. The Kappa coefficient and the McNemar test were used. Accuracy, sensitivity, specificity, and positive and negative predictive values (NPV and PPV, respectively) were calculated, as well as the effectiveness with cutoffs of 7 and 8 in identifying cervical intraepithelial neoplasm (CIN) 2+ when using the Swede score. Results The correlation between the 2 colposcopic indices was 79.41%. The Kappa coefficient and the McNemar p-value were 0.55 and 0.37, respectively. The IFCPC Nomenclature had sensitivity, specificity, accuracy, PPV, and NPV of 85.71, 55.00, 67.64, 57.14, and 84.61%, respectively. The Swede score had sensitivity, specificity, accuracy, PPV, and NPV of 100, 63.15, 79.41, 68.18, and 100%, respectively. A Swede score cutoff of 7 for CIN 2+ detection had a specificity of 94.73%, while with a cutoff of 8 it increased to 100%. The sensitivity for both values was 60%. The PPV and NPV for cutoffs of 7 and 8 were 90 and 75 and 100 and 76%, respectively. Conclusion Although both colposcopic indices have good reproducibility, the Swede score showed greater accuracy, sensitivity, and specificity in identifying CIN 2 + , especially when using a cutoff of 8.

Resumo Objetivo Avaliar a associação entre dois índices colposcópicos, o escore Swede e a Nomenclatura International Federation of Cervical Pathology and Colposcopy (IFCPC, na sigla em inglês) 2011, assim como determinar a eficácia do escore Swede com os pontos de corte 7 e 8. Métodos Trata-se de um estudo transversal, com 34 mulheres incluídas, que realizaram colposcopia com biópsia dirigida devido a uma citologia anormal. Os achados colposcópicos foram categorizados pelo escore Swede e pela Nomenclatura IFCPC 2011 e comparados um com o outro. Foram avaliados o coeficiente Kappa e o teste de McNemar e foram calculados a acurácia, a sensibilidade, a especificidade e valores preditivos negativos e positivos (VPN e VPP, respectivamente) de cada índice, assim como a eficácia com os pontos de corte 7 e 8 do escore Swede para determinar as lesões de neoplasia intraepitelial cervical (NIC) 2 + . Resultados A concordância entre os 2 índices foi de 79,41% e o coeficiente Kappa e o valor-p do teste de McNemar foram 0.55 e 0.37, respectivamente. Pela Nomenclatura IFCPC 2011, obtivemos como sensibilidade, especificidade, acurácia, VPP e VPN, respectivamente: 85,71, 55,00, 67,64, 57,14 e 84,61%. Pelo escore Swede obtivemos como sensibilidade, especificidade, acurácia, VPP e VPN, respectivamente: 100, 63,15, 79,41, 68,18 e 100%. O uso do escore Swede para detecção das lesões NIC 2+ obteve como especificidade 94,73% com o valor de corte de 7, enquanto o valor de corte 8 obteve 100%. A sensibilidade para ambos os cortes foi de 60%. O VPP e o VPN com os cortes 7 e 8 foram, respectivamente: 90,00 e 75,00 e 100,00 e 76,00%. Conclusão Ambos os índices colposcópicos tiveram boa reprodutibilidade; no entanto, o escore Swede mostrou melhor acurácia, sensibilidade e especificidade em identificar as lesões NIC 2+ e o melhor ponto de corte para identificar as lesões NIC2+ foi com o valor 8.

The prevalence and prognostic impact of tumor-infiltrating lymphocytes in uterine carcinosarcoma.

OBJECTIVE: To examine the prevalence and prognostic role of tumor microenvironment (TME) markers in uterine carcinosarcoma (UCS) through immunohistochemical characterization. METHODS: The internal database of our institution was queried out for women with UCS who underwent surgery and thereafter postoperative chemotherapy with carboplatin and paclitaxel between January 2012 and December 2017. Tissue microarrays containing surgical samples of UCS from 57 women were assessed by immunohistochemistry for CD3, CD4, CD8, FOXP3, PD-1, PD-L1, and PD-L2. RESULTS: The mean age was 65.3 years (range, 49 to 79 years). For the epithelial component (E), CD3_E and CD4_E were highly expressed in 38 (66.7%) and in 40 (70.1%) patients, respectively, and were significantly associated with more advanced stages (p = 0.038 and p = 0.025, respectively). CD8_E was highly expressed in 42 (73.7%) patients, FOXP3_E 16 (28.1%), PD-1_E 35 (61.4%), PD-L1_E 27 (47.4%) and PD-L2_E 39 (68.4%). For the sarcomatous component (S), the prevalence of high expression was: CD3_S 6 (10.5%), CD4_S 20 (35.1%), CD8_S 44 (77.2%), FOXP3_S 8 (14%), PD-1_S 14 (24.6%), PD-L1_S 14 (24.6%) and PD-L2_S 8 (14%). By multivariate analysis, the CD8/FOXP3_S ratio (p = 0.026), CD4_E (p = 0.010), PD-L1_E (p = 0.013) and PD-L1_S (p = 0.008) markers significantly influenced progression-free survival. CD4/FOXP3_S ratio (p = 0.043), PD-1_E (p = 0.011), PD-L1_E (p = 0.036) and PD-L1_S (p = 0.028) had a significant association with overall survival. CONCLUSION: Some differences in UCS clinical outcomes may be due to the subtype of TILs and PD-1/PD-L1 axis immune checkpoint signaling.

Prognostic Influence of Residual Tumor-Infiltrating Lymphocyte Subtype After Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

OBJECTIVE: This study aimed to examine the prevalence and prognostic role of tumor microenvironment (TME) in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) through immunohistochemical characterization. METHODS: The internal database of the Brazilian National Cancer Institute for women diagnosed with TNBC who underwent NACT and thereafter curative surgery between January 2010 and December 2014 was queried out. Core biopsy specimens and tissue microarrays containing surgical samples of TNBC from 171 and 134 women, respectively, were assessed by immunohistochemistry for CD3, CD4, CD8, CD14, CD56, CD68, CD117, FOXP3, PD-1, PD-L1, and PD-L2. Immune cell profiles were analyzed and correlated with response and survival. RESULTS: Mean age was 50.5 years, and most cases were clinical stage III [143 cases (83.6%)]. According to the multivariate analysis, only Ki67 and clinical stage significantly influenced the pattern of response to systemic treatment (p = 0.019 and p = 0.033, respectively). None of the pre-NACT IHC markers showed a significant association with event-free survival (EFS) or overall survival (OS). As for post-NACT markers, patients with high CD14 had significantly shorter EFS (p = 0.015), while patients with high CD3 (p = 0.025), CD4 (p = 0.025), CD8 (p = 0.030), CD14 (p = 0.015), FOXP3 (p = 0.005), high CD4/FOXP3 (p = 0.034), and CD8/FOXP3 (p = 0.008) showed longer EFS. Only high post-NACT CD4 showed significantly influenced OS (p = 0.038). CONCLUSION: The present study demonstrated that the post-NACT TIL subtype can be a determining factor in the prognosis of patients with TNBC.

Triple-Negative Breast Cancer: Assessing the Role of Immunohistochemical Biomarkers on Neoadjuvant Treatment.

OBJECTIVE: This study aimed to investigate the influence of immunohistochemical (IHC) biomarkers in the response to neoadjuvant chemotherapy (NACT) and survival outcomes in the subset of locally advanced triple-negative breast cancer (TNBC). MATERIALS AND METHODS: The epidermal growth factor receptor (EGFR), androgen receptor (AR), cytokeratins (CK5/6, CK14 and CK17), Ki67 and p53 immunohistochemistry were evaluated on 171 cases of TNBC submitted to NACT and subsequently to surgery. Intensity and percentage of the expression of these biomarkers were combined to formulate a specific score, that was correlated with prognostic features and assessed for survival outcomes. RESULTS: Most patients had advanced clinical-stage tumors (stage III: 83.6%; cT3/T4: 85.9%; cN1-3: 71.3%). The predominant histological subtype was high-grade (67.3%) and invasive ductal carcinoma (93.6%). The residual cancer burden (RCB) 0-1 corresponded to 28.7% of cases and low-risk lymph node ratio (LNR) represented 77.2%. High Ki67 expression only showed a significant correlation with grade 3 tumors (p = 0.0157). CK5/6 was observed in 16% (27/169), CK14 was positive in 10.1% (17/169), CK17 in 91.1% (153/168), p53 in 52.6% (70/133), EGFR in 92.9% (157/169 cases), AR in 13% (22/169) and Ki67 index was scored ≥40% in 57.9% (95/165). No IHC biomarker significantly impacted response or survival. Regarding the analysis of the outcomes of event-free survival (EFS) and overall survival (OS), clinical stage (p = 0.014 and p = 0.042, respectively), RCB (p < 0.0001 and p <0.0001, respectively) and LNR (p <0.0001 and p <0.0001, respectively) showed significant association. CONCLUSION: No IHC biomarker evaluated showed a significant association with a response or survival outcomes in TNBC patients. Clinical stage, LNR and RCB stood out for strongly influencing survival.

Human epidermal growth factor receptor 2 fluorescence in situ hybridization and P57KIP2 immunohistochemistry using tissue microarray: Improving histopathological subtyping of hydatidiform mole.

INTRODUCTION: Trophoblastic neoplasia is detected in approximately 25% of complete hydatidiform moles (CMs) and 0.5% of partial hydatidiform moles (PMs). Hydatidiform mole (HM) subtyping is important to properly monitor and predict patient outcomes. Ploidy studies generally involve diploid CMs and triploid PMs. P57KIP2, expressed in the maternal genome, is usually not detected in CM. We determined whether HER2 FISH and p57 immunostaining contributed to the histopathological classification of HMs. METHODS: This retrospective cohort study focused on patients diagnosed with HM by histopathological examination who were followed up at a trophoblastic disease center from 2002 to 2017. Pathological samples of 108 products of conception were reviewed and reclassified according to detailed criteria. Tissue microarray technology (TMA) was used for p57 KIP2 immunostaining and HER2 FISH analysis. RESULTS: Histopathological review showed 57 (53%) CMs, 47 (43%) PMs and 4 (4%) inconclusive cases. P57 immunostaining revealed 59 (55%) negative and 22 (20%) positive specimens, and 27 (25%) were inadequate for analysis. FISH HER2 detected 68 (63%) diploid and 33 (30%) triploid cases; two (2%) had oncogene amplification. The three strategies led to a diagnostic change in 28 samples (26%). The final diagnosis was CM in 75 cases (70%) and PM in 30 (28%); three cases remained inconclusive. DISCUSSION: TMA is a cost-saving method that allows the simultaneous study of large case series. The combination of histopathology, HER2 FISH and p57 tests can be useful for accurately differentiating CM and PM, thus providing additional information on disease prognosis.

Does the Sequence of Anthracycline and Taxane Matter? The NeoSAMBA Trial.

BACKGROUND: Taxanes usually follow anthracyclines in breast cancer neo/adjuvant treatment, likely because of their later introduction into clinical practice. However, there is no biological rationale that justifies this current standard of care. We compared a taxane followed by an anthracycline-based regimen with the reverse sequence in the neoadjuvant setting. PATIENTS AND METHODS: In a randomized, open-label, single-center phase II trial, women with inoperable, locally advanced, HER2-negative breast cancer were stratified by hormone receptor status and randomized to three cycles of docetaxel (T) followed by three cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus three cycles of FAC followed by three cycles of docetaxel. Surgery, radiotherapy, and adjuvant hormonal therapy were administered as per local guidelines. The primary endpoint was pathological complete response (pCR), and secondary endpoints included toxicity, event-free survival (EFS), and overall survival (OS). RESULTS: Treatment sequence did not improve pCR, which was 7% with T-FAC and 3% with FAC-T. However, after a median follow-up of 79 months, the 5-year EFS rate was 75.7% (95% confidence interval [CI], 65.4%-87.7%) with T-FAC and 48.2% (95% CI, 37.0%-62.7%) with FAC-T (hazard ratio [HR], 0.46; 95% CI, 0.26-0.81; log-rank p = .0054), and the 5-year OS rate was 89.7% (95% CI, 82.2%-97.8%) with T-FAC and 64.7% (95% CI, 53.6%-78.1%) with FAC-T (HR, 0.41; 95% CI, 0.22-0.78; p = .0052). There were no unexpected toxicities. CONCLUSION: We showed for the first time an improvement in EFS and OS with taxane-first compared with anthracycline-first sequencing chemotherapy in HER2-negative, locally advanced breast cancer. Confirmation of these results may have implications for clinical practice. This trial was registered with Clinicatrials.gov identifier NCT01270373. IMPLICATIONS FOR PRACTICE: The NeoSAMBA trial showed a benefit for taxane-first sequencing chemotherapy consistent with the systematic review of the literature as well as the larger Neo-tAnGo study. Many recent and current ongoing clinical trials have already followed this treatment strategy. As a taxane-before-anthracycline sequence carries neither an incremental cost nor an increased toxicity, and given the available literature on this issue, reinforced that taxane-first regimen can be easily incorporated into daily clinical practice while awaiting confirmation of these findings from larger trials.

NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells.

BACKGROUND: NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer. METHODS: The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990-1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3). RESULTS: NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter. CONCLUSIONS: In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis.

Breast cancer and neurofibromatosis type 1: a diagnostic challenge in patients with a high number of neurofibromas.

BACKGROUND: Neurofibromatosis 1 is one of the most common genetic diseases in humans, presenting with multiple neurofibromas and an increased risk of various benign and malignant tumors, including breast cancer. CASE PRESENTATION: In this paper we report a case of a woman with neurofibromatosis 1 and the challenge associated with detecting an advanced breast cancer because of numerous skin neurofibromas, which were responsible for a substantial delay in cancer diagnosis. Literature concerning the association of neurofibromatosis 1 and breast cancer is reviewed and discussed. CONCLUSIONS: Best practice guidelines for breast cancer detection are not sufficient for the screening of neurofibromatosis 1 carriers. A more intensive clinical and imaging approach should be used if the same early detection rate as in non-neurofibromatosis 1 women is to be achieved.

Anatomopathological characterization of placentas from HIV+ patients associated with p24 expression / Caracterização anatomopatológica da placenta de pacientes HIV+ associada à expressão do p24

INTRODUCTION: The study of placentas from pregnant human immunodeficiency virus (HIV) positive women has become the subject of numerous studies in the literature. Morphological, viral, immune and inflammatory placental aspects have been analyzed in order to grasp the vertical transmission of the virus. OBJECTIVE: To identify the most frequent findings in the placentas by associating them with a viral antigen and correlating them with the infection of newborns. MATERIAL AND METHODS: Thirty-five placentas from HIV- positive pregnant women were pathologically and immunohistochemically analyzed with the use of p24 antibody in the period from 1992 to1997 in accordance with the routine laboratory testing from the Anatomopathological Department - Hospital Universitário Antônio Pedro - Universidade Federal Fluminense (APD/HUAP/UFF). RESULTS: The microscopic alterations detected in all cases, including those with vertical transmission, were arteriopathy in the fetal blood circulation, chorioamnionitis, perivillous fibrin deposition, syncytial knotting, villous edema and villous immaturity. No specific macroscopic or histopathological changes were found in these placentas. The neonatal infection was observed in five cases. Vertical transmission was identified in two out of five placentas that had low weight for the respective stage of pregnancy. Immunohistochemical analysis revealed 14 positive cases, two of which showed vertical transmission. The viral protein was not identified in 10 out of 14 placentas from patients who had been medicated with zidovudine (AZT). CONCLUSION: Our study has contributed to the anatomopathological investigation into placentas from HIV-positive patients, although p24 expression per se did not allow a definite and early diagnosis of the vertical transmission.

INTRODUÇÃO: A importância do estudo da placenta de gestantes com o vírus da imunodeficiência humana (HIV) soropositivas tornou-se alvo de inúmeros trabalhos na literatura. Aspectos morfológicos, virais, imunes e inflamatórios intrínsecos ao tecido placentário foram analisados para o entendimento da transmissão vertical do vírus. OBJETIVO: Identificar as lesões mais frequentes nas placentas, associando-as ao antígeno viral e correlacionando-as com a infecção dos recém-nascidos. MATERIAL E MÉTODOS: Trinta e cinco placentas de gestantes HIV soropositivas foram analisadas por estudo anatomopatológico e imuno-histoquímico, utilizando o anticorpo p24, no período de 1992 a 1997, segundo a rotina do laboratório do Serviço Anatomia Patológica/Hospital Universitário Antônio Pedro/Universidade Federal Fluminense (SAP/HUAP/UFF). RESULTADOS: As alterações microscópicas registradas em todos os casos, inclusive nos de transmissão vertical, foram arteriopatia no circuito vascular fetal, corionamnionite, depósito fibrinoide perivilositário, excesso de nós sinciciais, edema do estroma viloso e dismaturidade vilosa. Nenhuma alteração microscópica ou macroscópica específica do HIV foi encontrada nas placentas. A infecção neonatal pôde ser constatada em cinco casos. A transmissão vertical foi identificada em duas placentas entre cinco que tinham baixo peso para a idade gestacional. Análise da imuno-histoquímica do p24 mostrou 14 casos positivos, dois dos quais apresentaram transmissão vertical. A proteína viral não foi identificada em 10 das 14 placentas cujas pacientes foram medicadas com zidovudina (AZT). CONCLUSÃO: Nosso estudo contribuiu para o estudo anatomopatológico da placenta de pacientes soropositivas para o HIV, porém a expressão do p24 por si só não permitiu um diagnóstico definitivo e precoce da transmissão vertical.

Two cases of male breast cancer at a university hospital in southeast Brazil.

We report two rare cases of breast cancer in men treated with modified radical mastectomy. The patients were aged 67 and 45 years at the time of diagnosis. Tumor sizes were 2 cm and 8 cm in the older and younger patient, respectively. The histopathologic diagnosis was infiltrating ductal carcinoma in the first patient and infiltrating papillary carcinoma in the second patient. Immunohistochemical tests demonstrated estrogen and progesterone receptor positivity and HER2/c-erbB-2 negativity in both cases. The rarity of these cases is noted, in view of their uncommon occurrence at an early age in men and their immunophenotypic positivity, similar to breast cancer in women.

Concordance between cytopathology and incisional biopsy in the diagnosis of oral squamous cell carcinoma

Oral cytopathology is a simple, non-invasive technique that could be used for early detection of oral premalignant and malignant lesions, but the effectiveness of this diagnostic approach remains controversial. The aim of this study was to evaluate the sensitivity, specificity, positive and negative predictive values, and accuracy of cytopathology for diagnosing oral squamous cell carcinoma (OSCC) and the diagnostic concordance between cytopathological and histopathological diagnoses. The study enrolled 172 patients at outpatient clinics who presented with oral lesions suspicious of malignancy. All patients underwent oral cytological scrapes followed by an incisional biopsy. Of 148 cases that were histopathologically diagnosed with OSCC, the cytopathological method diagnosed 123 positive cases and resulted in a suspicion of OSCC in 16 patients. Based on these data, the sensitivity was 83.1%, the specificity was 100.0%, the positive predictive value was 100.0%, the negative predictive value was 49.0%, and the accuracy was 85.5%. The diagnostic concordance between histopathological and cytopathological examinations was 83.1% for OSCC and 85.7% for non-neoplastic lesions. The results indicate that cytopathological diagnosis had good concordance with histopathological diagnosis and showed high sensitivity, specificity, positive predictive value, and accuracy. We conclude that the sensitivity of oral cytopathology is sufficient to justify its use as a diagnostic screening test and to confirm the malignant nature of epithelial cells, mainly for the classification of OSCC. Therefore, cytopathology may be a reliable method for referring patients who require diagnosis of suspected oral cancer for starting treatment.

Concordance between cytopathology and incisional biopsy in the diagnosis of oral squamous cell carcinoma.

Oral cytopathology is a simple, non-invasive technique that could be used for early detection of oral premalignant and malignant lesions, but the effectiveness of this diagnostic approach remains controversial. The aim of this study was to evaluate the sensitivity, specificity, positive and negative predictive values, and accuracy of cytopathology for diagnosing oral squamous cell carcinoma (OSCC) and the diagnostic concordance between cytopathological and histopathological diagnoses. The study enrolled 172 patients at outpatient clinics who presented with oral lesions suspicious of malignancy. All patients underwent oral cytological scrapes followed by an incisional biopsy. Of 148 cases that were histopathologically diagnosed with OSCC, the cytopathological method diagnosed 123 positive cases and resulted in a suspicion of OSCC in 16 patients. Based on these data, the sensitivity was 83.1%, the specificity was 100.0%, the positive predictive value was 100.0%, the negative predictive value was 49.0%, and the accuracy was 85.5%. The diagnostic concordance between histopathological and cytopathological examinations was 83.1% for OSCC and 85.7% for non-neoplastic lesions. The results indicate that cytopathological diagnosis had good concordance with histopathological diagnosis and showed high sensitivity, specificity, positive predictive value, and accuracy. We conclude that the sensitivity of oral cytopathology is sufficient to justify its use as a diagnostic screening test and to confirm the malignant nature of epithelial cells, mainly for the classification of OSCC. Therefore, cytopathology may be a reliable method for referring patients who require diagnosis of suspected oral cancer for starting treatment.

O decréscimo vertiginoso das autópsias em um hospital universitário do Brasil nos últimos 20 anos / The dramatic decline of the autopsies at a Brazilian university hospital in the last 20 years

INTRODUÇÃO: O declínio no número de autópsias em hospitais e instituições universitárias é evento amplamente reportado, inicialmente em países do primeiro mundo e posteriormente em muitos países em desenvolvimento, como o Brasil. As causas para essa tendência são múltiplas e complexas, incluindo aspectos religiosos, familiares e médicos. Entre estes últimos, salientam-se razões diagnósticas, caracterizadas pelo significativo avanço tecnológico na imagenologia, com a suposição de que todos os diagnósticos agora podem ser feitos em vida, e a crescente ansiedade de processos judiciais contra médicos por má prática. OBJETIVO: Demonstrar o decréscimo vertiginoso e drástico do número de autópsias em um hospital universitário no Brasil. MATERIAL E MÉTODO: Avaliou-se o número de registros nos livros de autópsias consecutivas realizadas no Departamento de Patologia do Hospital Universitário Antonio Pedro da Universidade Federal Fluminense (HUAP/UFF), Niterói, Rio de Janeiro, criando um banco dados em tabela do programa Microsoft Excel. RESULTADOS: Durante os anos 1966 a 2009, foram realizadas 23.813 necrópsias, sendo 12.702 de adultos e 11.111 de fetos. Entre os anos 1966 e 1998, foram realizadas mais necrópsias, no total de 23.321, sendo 12.482 de adultos e 10.839 de fetos. Já entre os anos 1999 e 2009, foi observado o declínio acentuado e drástico das mesmas, totalizando apenas 492 necrópsias, sendo 220 de adultos e 272 de fetos. CONCLUSÃO: Acreditamos que a principal causa para esse declínio é a pouca informação da população, que desconhece que o saber é fruto de estudo, pesquisa, prática e aprimoramento.

INTRODUCTION: The decline in the number of autopsies at hospitals and university hospitals has been widely reported, initially in developed countries and afterwards in several developing countries including Brazil. The causes for this trend are multiple and complex, encompassing religious, family and medical aspects. Among the latter, we highlight diagnostic reasons, which are characterized by major technological advances in clinical imaging associated with the underlying assumption that all diagnoses can currently be made before death. Furthermore, there is a growing concern about malpractice lawsuits. OBJECTIVE: To demonstrate the sharp decrease in the number of autopsies at a university hospital in Brazil. MATERIAL AND METHODS: We evaluated the number of autopsies conducted at the Pathology Department of Antonio Pedro University Hospital (HUAP), Niterói, Rio de Janeiro, and a database spreadsheet was created at Microsoft Excel. RESULTS: From 1966 to 2009, 23,813 autopsies were performed, comprising 12,702 adults and 11,111 fetuses. The highest number of autopsies occurred from 1966 to 1998, when 23,321 autopsies were performed, comprising 12,482 adults and 10,839 fetuses. Whereas, there was a dramatic decline from 1999 to 2009, when 492 autopsies were performed, including 220 adults and 272 fetuses. CONCLUSION: We believe that the main cause of this reduction is the lack of information among laypeople and medical professionals, who have neglected the fact that knowledge is ultimately acquired through study, investigation and practice.

Investigação da LMP1 do EBV e a coinfeçcão do HPV em lesões genitais de pacientes infectados ou não pelo HIV / Investigation of the LMP1 EBV and co-infection by HPV in genital lesions of patients infected or not by HIV

INTRODUÇÃO: Vários estudos têm demonstrado associação do vírus Epstein-Barr (EBV) com neoplasias malignas, inclusive genitais, em que o papilomavírus humano (HPV) é o principal vírus associado às neoplasias epiteliais benignas e malignas. OBJETIVO: Investigar a presença do EBV e do HPV em lesões genitais de ambos os sexos, em pacientes soropositivos (grupo A) ou não (grupo B) para o vírus da imunodeficiência humana (HIV). MATERIAL E MÉTODO: Selecionados 126 pacientes e 135 lesões anogenitais, sendo 67 pacientes (53 por cento) e 75 lesões (56 por cento) no grupo A e 59 pacientes (47 por cento) e 60 lesões (44 por cento) no grupo B, para análise imuno-histoquímica (IHQ) por meio dos anticorpos monoclonais antiproteína latente de membrana 1 (LMP1) e HPV (DAKO®). RESULTADOS: A análise mostrou que o número total de lesões com imunopositividade para o HPV e para a LMP1 foi maior no grupo A (32 e 35, respectivamente) quando comparado ao B (16 e seis, respectivamente). A análise estatística (nível de significância de 5 por cento) mostrou que as proporções para o HPV não são estatisticamente significativas (z = 1,93; valor p = 0,053). Entretanto, para a LMP1, a diferença (47 por cento no grupo A e 10 por cento no B) é significativa (z = 4,60; valor p = 4,2×10-6). Do mesmo modo, a associação HPV-LMP1 (21 por cento no grupo A e 7 por cento no B) também mostrou diferença estatisticamente significativa (z = 2,38; valor p = 0,017). CONCLUSÃO: Esses resultados indicam a possibilidade de sinergismo da infecção pelo EBV e a coinfecção EBV-HPV em lesões epiteliais genitais, particularmente em pacientes soropositivos para o HIV. Entretanto, investigações com metodologia de maior especificidade e sensibilidade são necessárias para a verificação da real participação do EBV na patogênese de lesões epiteliais genitais.

INTRODUCTION: Several studies have demonstrated the association between Epstein-Barr virus (EBV) and malignant neoplasias, including genital lesions, in which the human papillomavirus (HPV) is the main virus associated with both benign and malignant epithelial neoplasias. OBJECTIVE: Investigate the presence of EBV and HPV in genital lesions in HIV-infected patients (group A) or HIV non-infected patients (group B) from both genders. MATERIAL AND METHOD: We selected 126 patients and 135 anogenital lesions, comprising 67 patients (53 percent) and 75 lesions (56 percent) from group A and 59 patients (47 percent) and 60 lesions (44 percent) from group B, to histopathological and immunohistochemical analyses through latent membrane protein 1 (LMP1) monoclonal antibodies and HPV (DAKO®). RESULTS: The analysis showed that the total number of lesions with immunopositivity for HPV and for LMP1 was higher in group A (32 and 35 respectively) in comparison with B (16 and six respectively). Statistical analysis (significance level of 5 percent) showed that the proportions for HPV are not statistically significant (z = 1.93; value p = 0.053). However, the difference (47 percent in group A and 10 percent in B) is significant for LMP1 (z = 4.60; value p = 4.2×10-6). Similarly, the association of HPV and LMP1 (21 percent in group A and 7 percent in B) also showed a significant statistical difference (z = 2.38; value p = 0.017). CONCLUSION: The results demonstrated the possibility of synergism between EBV infection and EBV-HPV co-infection in genital epithelial lesions, mainly among HIV-infected patients. However, further investigations with a more specific and sensitive methodology are required in order to assess the real influence of EBV on the pathogenesis of genital epithelial lesions.