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Very little information is available on the mutational landscape of vulvar squamous cell carcinoma (VSCC), a disease that mainly affects older women. Studies focusing on the mutational patterns of the currently recognized etiopathogenic types of this tumor [human papillomavirus (HPV)-associated (HPV-A), HPV-independent (HPV-I) with TP53 mutation (HPV-I/TP53mut), and HPV-I with wild-type TP53 (HPV-I/TP53wt]) are particularly rare, and there is almost no information on the prognostic implications of these abnormalities. Whole-exome DNA sequencing of 60 VSCC and matched normal tissues from each patient was performed. HPV detection, immunohistochemistry (IHC) for p16, p53, and mismatch repair proteins were also performed. Ten tumors (16.7%) were classified as HPV-A, 37 (61.7%) as HPV-I/TP53mut, and 13 (21.6%) as HPV-I/TP53wt. TP53 was the most frequently mutated gene (66.7%), followed by FAT1 (28.3%), CDKN2A (25.0%), RNF213 (23.3%), NFE2L2 (20%) and PIK3CA (20%). All the 60 tumors (100%) were DNA mismatch repair proficient. Seventeen tumors (28.3%) showed CCND1 gain. Bivariate analysis, adjusted for FIGO stage, revealed that TP53 mutation, CCND1 gain, and the combination of the two alterations were strongly associated with impaired recurrence-free survival (hazard ratio=4.4, p<0.001) and disease-specific survival (hazard ratio=6.1, p=0.002). Similar results were obtained when p53 IHC status was used instead of TP53 status and when considering only HPV-I VSCC. However, in the latter category, p53 IHC maintained its prognostic impact only in combination with CCND1 gains. All tumors carried at least one potentially actionable genomic alteration. In conclusion, VSCCs with CCND1 gain represent a prognostically adverse category among HPV-I/TP53mut tumors. All patients with VSCCs are potential candidates for targeted therapy.
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Two pathways have been described for vulvar squamous cell carcinomas (VSCC), one associated with human papillomavirus (HPV), and the other HPV-independent. We compared the etiopathogenic features of a series of VSCC from Mozambique, a sub-Saharan country with high prevalence of HPV and HIV, with those of Spain, a European country with low prevalence of HPV and HIV. All VSCC diagnosed at the two institutions from January 2018 to December 2020 were included (n = 35 and n = 41, respectively). HPV DNA detection and genotyping, and immunohistochemistry for p16 and p53 were performed. Tumors showing p16 positive staining and/or HPV DNA positivity were considered HPV-associated. 34/35 tumors (97%) from Mozambique and 8/41 (19%) from Spain were HPV-associated (P < .001). Mean age of the patients from Mozambique and Spain was 45 ± 12 and 72 ± 14, respectively (P < .001). No differences were found in terms of HPV genotypes or multiple HPV infection rates. 1/35 tumors (3%) from Mozambique and 29/41 (70%) from Spain showed abnormal p53 immunostaining (P < .001). In contrast with the predominance of HPV-independent VSCC affecting old women in Europe, most VSCC in sub-Saharan Africa are HPV-associated and arise in young women. This data may have important consequences for primary prevention of VSCC worldwide.
Assuntos
Carcinoma de Células Escamosas , Infecções por HIV , Infecções por Papillomavirus , Neoplasias Vulvares , Humanos , Feminino , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/diagnóstico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Vulvares/epidemiologia , Neoplasias Vulvares/etiologia , Neoplasias Vulvares/diagnóstico , Papillomaviridae/genética , Papillomaviridae/metabolismo , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Infecções por HIV/complicações , Moçambique/epidemiologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismoRESUMO
Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with dual pathogenesis, Human papillomavirus (HPV)-associated and HPV-independent, with a poorly explored molecular landscape. We aimed to summarize the findings of the series analyzing molecular hallmarks of this neoplasm. In January 2021, we conducted a comprehensive literature search using Pubmed Medline and Scopus to identify publications focused on genomic profiling of VSCC. Observational studies, including both prospective and retrospective designs, evaluating molecular alterations in VSCC were deemed eligible. A total of 14 studies analyzing 749 VSCC were identified. The study series were heterogeneous in HPV testing and sequencing strategies, included small sets of tumors and cancer genes, and commonly lacked survival analysis. Only one extensive targeted next-generation sequencing-based study comprised a large cohort of 280 VSCC. The mutated genes, their number, and frequencies were highly variable between the series. Overall, TP53 and CDKN2A, followed by PIK3CA, HRAS, and PTEN, were the most frequently studied and mutated genes. Mutations involved in the PI3K/AKT/mTOR pathway, including TP53, HRAS, KRAS, and PIK3CA, have been consistently reported across the studies. However, the role of individual mutations or pathways in the development of VSCC remains unclear. In conclusion, heterogeneity and the small sample size of available molecular series contribute to a limited view of the molecular landscape of VSCC. Large-scale genome- or exome-wide studies with robust HPV testing are necessary to improve the molecular characterization of VSCC.
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Carcinoma de Células Escamosas/genética , Mutação , Proteínas de Neoplasias/genética , Neoplasias Vulvares/genética , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias Vulvares/metabolismoRESUMO
Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.
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Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/genética , Neoplasias Penianas/etiologia , Neoplasias Penianas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Variações do Número de Cópias de DNA/genética , Geografia , Humanos , Masculino , Terapia de Alvo Molecular , Mutação/genética , Papillomaviridae/fisiologia , Neoplasias Penianas/patologia , Neoplasias Penianas/virologia , Prognóstico , Transdução de SinaisRESUMO
Penile squamous cell carcinoma (PSCC) is classified into 2 prognostically distinct types: human papillomavirus (HPV)-associated and HPV-independent. However, the impact of p53 status on prognosis remains controversial. We correlated HPV and p53 status with the prognosis of a large series of patients with PSCC. p53 was analyzed according to a recently described immunohistochemical (IHC) pattern-based framework that includes 2 normal and 4 abnormal patterns and closely correlates with TP53 mutational status. A total of 122 patients with surgically treated PSCC in 3 hospitals were included. Based on HPV in situ hybridization and p16 and p53 IHC, the tumors were classified into 3 subtypes: HPV-associated, HPV-independent/p53 normal, and HPV-independent/p53 abnormal. All patients were followed up for at least 22 months (median: 56.9 months). Thirty-six tumors (29%) were HPV-associated, 35 (29%) were HPV-independent/p53 normal, and 51 (42%) were HPV-independent/p53 abnormal. Disease-related deaths were observed in 3/36 (8%), 0/35 (0%) and 14/51 (27%) of the patients, respectively (P< 0.001). A total of 7/14 deaths in the latter group were patients with tumors showing p53 abnormal patterns not recognized in the classic p53 IHC interpretation (basal, null, and cytoplasmic). According to our multivariate analysis, HPV-independent/p53 abnormal tumors and advanced stage were associated with impaired disease-specific survival (hazard ratio = 23.4, 95% CI = 2.7-3095.3; P= 0.001 and 16.3, 95% CI = 1.8-2151.5; P= 0.008, respectively). In conclusion, compared with patients with HPV-associated and HPV-independent/p53-normal PSCC, patients with HPV-independent/p53 abnormal PSCC have worse clinical outcomes. p53 IHC results define 2 prognostic categories in HPV-independent PSCC: HPV-independent/p53-normal tumors as low-risk tumors, whereas HPV-independent/p53-abnormal tumors as aggressive neoplasms.
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BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.
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PTEN Fosfo-Hidrolase , Proteínas de Ligação a Retinoblastoma , Proteína Supressora de Tumor p53 , Humanos , Masculino , PTEN Fosfo-Hidrolase/genética , Estudos Retrospectivos , Idoso , Prognóstico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Pessoa de Meia-Idade , Transcriptoma , Metástase Neoplásica , Antagonistas de Androgênios/uso terapêutico , Idoso de 80 Anos ou mais , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologiaRESUMO
The recent addition of novel immunotherapy drugs for the treatment of urothelial carcinoma makes it necessary the establishment of criteria to harmonize the immunohistochemical assessment of PD-L1, both as a prognostic factor and for the selection of patients to be treated. In this scenario, a group of uropathologists from the Spanish Society of Pathological Anatomy, together with a medical oncologist as an external collaborator subspecialized in uro-oncology, have prepared this document of recommendations based on the available evidence. During PD-L1 assessment it is especially relevant the selection of the sample, its processing, the immunohistochemical platform and antibody used, and the algorithm applied in the interpretation of results. All these aspects must be indicated in the results report, which should be easily interpretable in a context of rapid evolution of immunological therapies.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/terapia , Carcinoma de Células de Transição/terapia , Antígeno B7-H1 , Consenso , Imunoterapia/métodosRESUMO
p53 immunohistochemistry (IHC) has been proposed as a surrogate for TP53 mutations in penile squamous cell carcinomas (PSCC). We aimed to evaluate the performance of a pattern-based evaluation of p53 IHC in PSCC. Human papilloma virus (HPV) DNA testing, p16 and p53 IHC, and whole exome sequencing were performed in a series of 40 PSCC. p53 IHC was evaluated following a pattern-based framework and conventional p53 IHC evaluation. Out of 40 PSCC, 12 (30.0%) were HPV-associated, and 28 (70.0%) were HPV-independent. The agreement between the p53 IHC pattern-based evaluation and TP53 mutational status was almost perfect (k = 0.85). The sensitivity and accuracy of the pattern-based framework for identifying TP53 mutations were 95.5% and 92.5%, respectively, which were higher than the values of conventional p53 IHC interpretation (54.5% and 70.0%, respectively), whereas the specificity was the same (88.9%). In conclusions, the pattern-based framework improves the accuracy of detecting TP53 mutations in PSCC compared to the classical p53 IHC evaluation.
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Penile squamous cell carcinomas (PSCC) are classified by the World Health Organization into two categories based on their relationship with the human papillomavirus (HPV): HPV-associated and HPV-independent. We compared a cohort of PSCC from Mozambique, a sub-Saharan country in southeast Africa with a high prevalence of HPV and HIV infection, and Spain, a country in southwestern Europe with a low prevalence of HPV and HIV, to study the distribution of the etiopathogenic categories of these tumors in both sites. A total of 79 PSCC were included in the study (28 from Mozambique and 51 from Spain). All cases underwent HPV-DNA polymerase chain reaction (PCR) testing, genotyping, and immunohistochemistry for p16 and p53. Any PSCC showing either p16 overexpression or HPV-DNA in PCR analysis was considered HPV-associated. Overall, 40/79 (50.6%) tumors were classified as HPV-associated and 39 (49.4%) as HPV-independent. The two sites showed marked differences: 25/28 (89.3%) tumors from Mozambique and only 15/51 (29.4%) from Spain were HPV-associated (p < 0.001). HPV16 was the most frequent HPV type identified in 64.0% (16/25) of the HPV-associated tumors from Mozambique, and 60.0% (9/15) from Spain (p = 0.8). On average, patients from Mozambique were almost two decades younger than those from Spain (mean age 50.9 ± 14.9 and 69.2 ± 13.3, respectively [p < 0.001]). In conclusion, significant etiopathogenic differences between PSCC in Mozambique and Spain were observed, with a remarkably high prevalence of HPV-associated tumors in Mozambique and a relatively low prevalence in Spain. These data may have important consequences for primary prevention of PSCC worldwide.
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Most human papillomavirus (HPV)-independent penile squamous cell carcinomas (PSCCs) originate from an intraepithelial precursor called differentiated penile intraepithelial neoplasia, characterized by atypia limited to the basal layer with marked superficial maturation. Previous studies in vulvar cancer, which has a similar dual etiopathogenesis, have shown that about one fifth of HPV-independent precursors are morphologically indistinguishable from high-grade squamous intraepithelial lesions (HSILs), the precursor of HPV-asssociated carcinomas. However, such lesions have not been described in PSCC. From 2000 to 2021, 55 surgical specimens of PSCC were identified. In all cases, thorough morphologic evaluation, HPV DNA detection, and p16, p53, and Ki-67 immunohistochemical (IHC) staining was performed. HPV-independent status was assigned based on both negative results for p16 IHC and HPV DNA. Thirty-six of the 55 PSCC (65%) were HPV-independent. An intraepithelial precursor was identified in 26/36 cases (72%). Five of them (19%) had basaloid features, morphologically indistinguishable from HPV-associated HSIL. The median age of the 5 patients was 74 years (range: 67 to 83 y). All 5 cases were p16 and DNA HPV-negative. Immunohistochemically, 3 cases showed an abnormal p53 pattern, and 2 showed wild-type p53 staining. The associated invasive carcinoma was basaloid in 4 cases and the usual (keratinizing) type in 1. In conclusion, a small proportion of HPV-independent PSCC may arise on adjacent intraepithelial lesions morphologically identical to HPV-associated HSIL. This unusual histologic pattern has not been previously characterized in detail in PSCC. p16 IHC is a valuable tool to identify these lesions and differentiate them from HPV-associated HSIL.
Assuntos
Carcinoma in Situ , Neoplasias Penianas , Neoplasias Cutâneas , Lesões Intraepiteliais Escamosas , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/patologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Masculino , Papillomaviridae/genética , Infecções por Papillomavirus/patologia , Neoplasias Penianas/patologia , Neoplasias Cutâneas/patologia , Lesões Intraepiteliais Escamosas/patologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3'-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3'-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3'-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.
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The diagnostic problems in the subtyping of renal tumors were evaluated by a panel of five pathologists studying a set of selected tumors. Five pathologists independently assessed a single hematoxylin-and-eosin (HE)-stained slide from 28 selected renal tumors. After this independent assessment, the pathologists reevaluated and discussed all discordant cases. Additional HE-stained sections and immunohistochemically (IHC) stained slides were available. The generalized kappa for interobserver agreement was calculated. After independent assessment of the HE-stained slides, the five pathologists unanimously reached an agreement in the decision between malignant and benign in 82% of the cases. Fifty percent of the cases were correctly subclassified. The overall generalized kappa value for the five pathologists was 0.320 (CI 95% 0.090-0.551), which is considered a moderate agreement. A 100% agreement was reached for all 28 cases after examination of more slides from different tumor areas and IHC-stained sections. An accurate histologic distinction between benign and malignant renal tumors is possible on one HE-stained section. Correct assignment of the subtype is difficult on one slide alone and relies on IHC-markers and additional slides. Tumors composed of an eosinophilic cell type and tumors with a papillary growth pattern were the major causes of an incorrect diagnosis on an HE-stained section alone.
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Carcinoma de Células Renais/patologia , Erros de Diagnóstico/prevenção & controle , Neoplasias Renais/patologia , Idoso , Biópsia , Carcinoma de Células Renais/classificação , Corantes , Amarelo de Eosina-(YS) , Feminino , Hematoxilina , Humanos , Imuno-Histoquímica , Neoplasias Renais/classificação , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Coloração e Rotulagem/métodosRESUMO
PURPOSE: To evaluate the PCA3 (Prostate Cancer 3 gene) as a tool to improve prostate cancer (PCa) screening and its capability to predict PCa aggressiveness. PATIENTS AND METHODS: A retrospective study with data from consecutive patients with suspected PCa seen in the urology department between November 2009 and April 2016 and who were candidates for prostate biopsy. A total of 1038 urine samples were tested in our laboratory with a kit that generated a PCA3 score (s-PCA3). A prostate biopsy was recommended only in those patients with s-PCA3≥35. Associations between variables were analyzed using the R software. RESULTS: In patients with a positive s-PCA3 (44.5%), a subsequent biopsy was recommended. Of a total of 151 biopsies studied, 56.3% yielded a diagnosis of PCa. The probability of a positive biopsy increased as the s-PCA3 increased (p=0.041). The percentage of affected cylinders increased as the s-PCA3 increased (p=0.015). A statistically significant relationship was observed between s-PCA3 and both the Gleason score and the Grade Group (p=0.001 and 0.008, respectively). The best log-linear models and a logistic model confirmed the relationships shown previously with Fisher's exact tests. CONCLUSIONS: S-PCA3 may serve as an additional marker to reduce the indication for biopsies and avoid overdiagnosis and overtreatment of patients with suspected PCa. The prognostic significance of s-PCA3 was confirmed, as it was associated with tumor volume and Gleason score. Importantly, to our knowledge this is the first time that an association has been demonstrated between s-PCA3 and the new Grade Group.
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Antígenos de Neoplasias/urina , Próstata/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/urina , RNA Mensageiro/urina , Idoso , Antígenos de Neoplasias/genética , Biópsia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Humanos , Modelos Lineares , Masculino , Gradação de Tumores , Estudos RetrospectivosRESUMO
The stem (basal) cells of prostate acini are considered the origin of prostate cancer. Between these cells and the final secretory cells, different intermediate or transit cells can be observed, and every one of them can evolve into malignant cells, explaining the biological variability of prostatic cancer. The exact changes between normal gland and prostatic intraepithelial neoplasia (PIN) are not yet known, but a post-inflammatory atrophy lesion is being studied in this respect. The PIN lesion is considered the pre-invasive change of prostatic cancer and its presence in needle biopsy is clinically used for follow-up of the patient. The progressive knowledge of the stromal invasion in prostate cancer (loss of some cell-cell adhesion molecules and expression of others) can be correlated with the Gleason grading system, and the molecular changes in the progression to androgen-independent carcinoma can be used as a prognostic marker in conjunction with the classical pathological markers.
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Lesões Pré-Cancerosas/patologia , Próstata/patologia , Hiperplasia Prostática/patologia , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/patologia , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Progressão da Doença , Humanos , Masculino , Invasividade Neoplásica/patologiaRESUMO
The diagnosis of prostate cancer is made based on the architecture of the glandular proliferation and nuclear atypia, but some normal structures (seminal vesicle, Cowper's glands, prostatic central zone) or nonneoplastic proliferative lesions can mimic carcinoma. Of the 3 patterns of prostate cancer--solid, cribriform, and microglandular, the microglandular pattern is the one that imitates carcinoma most frequently on needle biopsy. The demonstration of basal cells can be the best method to identify these prostate cancer mimickers.
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Próstata/patologia , Doenças Prostáticas/diagnóstico , Neoplasias da Próstata/diagnóstico , Biópsia por Agulha , Diagnóstico Diferencial , Humanos , MasculinoRESUMO
The coexpression of HER2 and EGFR L858R in a solitary nodule removed from the lung, whose mutation was not confirmed by molecular techniques, made us think about the possible existence of a cross-reaction between HER2 and the EGFR L858R-specific antibody. Our study was designed to further analyze the existence of this cross-reaction and stress the need to exclude a metastatic breast cancer when dealing with EGFR L858R-positive cases. The series consists of 42 primary breast carcinomas, 22 HER2 positive for overexpression and amplification, and 20 negative for both. EGFR mutations were studied by immunohistochemistry and confirmed using real-time PCR when positive. Immunohistochemistry assay with EGFR L858R was positive in 19 (86%) of the HER2-positive breast carcinomas and negative in all HER2-negative carcinomas. The EGFR L858R antibody gives false-positive results in most of the breast carcinomas with HER2 overexpression/amplification. As a consequence, it is essential to confirm any EGFR L858R-positive cases by molecular methods or at least discard the presence of HER2 overexpression/amplification before rendering a diagnosis. It is also important to consider that HER2 has been described in other carcinomas such as urothelial, gastric or ovarian, as well as lung, although infrequently.
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Neoplasias da Mama/metabolismo , Receptores ErbB/metabolismo , Genes erbB-2 , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Reações Cruzadas , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
ERG gene rearrangement has been identified as a highly specific alteration that is present in 40-50 % of prostate carcinomas. The standardization of an immunohistochemical assay with a novel anti-ERG antibody recently described would have significant diagnostic value. The aims of this study were to identify the incidence of this rearrangement in a Spanish population and to test the specificity of immunohistochemical ERG evaluation for prostate carcinomas. Three prostate tissue microarrays were constructed using radical prostatectomy specimens and related to grade, local invasion, and regional invasion. In addition to samples from malignant cases (160), specimens of prostatic hyperplasia (26) and high-grade prostatic intraepithelial neoplasia (10) were included. Tissue microarrays of 270 samples from most common malignant tumors (breast, colon, lung, and bladder) were also tested. All were analyzed by immunohistochemistry. Seventy-five out of 154 evaluable cases (49 %) of prostate carcinoma showed ERG expression; 52/75 showed strong staining. No ERG expression was observed in any of the high-grade prostatic intraepithelial neoplasia. ERG expression was independent of Gleason score (p = 0.160), extent of invasion (p = 0.517), and regional lymph node involvement (p = 0.816). No ERG expression was found in any other type of tumor, with the exception of one bladder cancer sample that showed focal and weak expression. The frequency of ERG detected in our study correlated with the results published for other Caucasian populations. Strong ERG protein expression was exclusively detected in prostate carcinomas, corroborating the specificity of ERG rearrangements for these tumors. Thus, detecting ERG using immunohistochemistry may be useful in routine practice in pathology departments.
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Adenocarcinoma/metabolismo , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/metabolismo , Transativadores/metabolismo , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Rearranjo Gênico , Humanos , Imuno-Histoquímica/métodos , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prostatectomia , Neoplasia Prostática Intraepitelial/secundário , Neoplasias da Próstata/patologia , Espanha , Análise Serial de Tecidos , Regulador Transcricional ERGRESUMO
High microsatellite instability (MSI-H) allows the identification of a subset of colorectal carcinomas associated with good prognosis and a higher incidence of Lynch syndrome. The aim of this work was to assess the interobserver variability and optimize our MSI-H prediction model previously published based on phenotypic features.The validation series collected from five different hospitals included 265 primary colorectal carcinomas from the same number of patients. The eight clinicopathological parameters that integrate our original model were evaluated in the corresponding centers. Homogeneity assessment revealed significant differences between hospitals in the estimation of the growth pattern, presence of Crohn-like reaction, percentage of cribriform structures, and Ki-67 positivity. Despite this observation, our model was globally able to predict MSI-H with a negative predictive value of 97.0%. The optimization studies were carried out with 615 cases and resulted in a new prediction model RERtest8, which includes the presence of tumor infiltrating lymphocytes at the expense of the percentage of cribriform structures. This refined model achieves a negative predictive value of 97.9% that is maintained even when the immunohistochemical parameters are left out, RERtest6. The high negative predictive value achieved by our models allows the reduction of the cases to be tested for MSI to less than 10%. Furthermore, the easy evaluation of the parameters included in the model renders it a useful tool for the routine practice and can reinforce other published models and the current clinical protocols to detect the subset of colorectal cancer patients bearing hereditary nonpolyposis colorectal cancers risk and/or MSI-H phenotype.
Assuntos
Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Idoso , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Fine needle aspiration (FNA) cytology is under consideration as an auxiliary preoperative diagnostic technique in the diagnosis of renal masses. However, reports for FNA are contradictory with regard to diagnostic accuracy and applicability. OBJECTIVE: To evaluate the diagnostic accuracy and reproducibility of FNA from renal masses. DESIGN: FNAs performed in-bench (hematoxylin and eosin [H&E] stains) from 66 consecutive renal tumours (58 malignant and 8 benign tumours) were presented twice with a 6-mo interval to five pathologists with little experience in renal cytology. Pathologists were blinded for the results of the first round as well for the surgical specimen. The FNAs were stained for Papanicolaou and Giemsa. MEASUREMENTS: Diagnostic accuracy, concordance between smears and surgical specimens, and the generalized kappa for interobserver/intraobserver agreement were calculated. RESULTS AND LIMITATIONS: The number of nondiagnostic and nonconclusive cases ranged from 5-14% in the first and 3-8% in the second round. Overall accuracy varied between 73-89% and 71-91% for the first and second round, respectively. Sensitivity (72-97%) and positive predictive value (PPV) (93-100%) to classify a malignant tumour in both rounds was high. Sensitivity (25-100%) and PPV (28-100%) to classify a benign tumour was lower with a wide confidence interval. Overall concordance in subtyping ranged from 39-70% in the first, and from 52-74% in the second round. Interobserver agreement ranged from fair (kappa=0.039) to substantial (kappa=0.540) for the different subtypes. The intraobserver agreement (mean kappa=0.357, CI 95%=0.304-0.411) was moderate for all pathologists. The low number of benign tumours in this study precludes sound statements regarding the diagnostic accuracy of FNA to classify benignity. CONCLUSION: Despite the lack of experience in renal cytology, all pathologists showed a high diagnostic yield and good overall accuracy in distinguishing between malignant and benign tumours. Concordance in subtyping varied widely among pathologists and was reliable only for clear cell renal cell carcinoma (ccRCC). These results suggest that FNA may have a potential role in the diagnosis of renal tumours although its value in subtyping was limited in our setting.
Assuntos
Biópsia por Agulha Fina , Neoplasias Renais/patologia , Rim/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
AIM: To evaluate the diagnostic feasibility and reproducibility of immediate postcryoablation biopsies of small renal masses. MATERIALS AND METHODS: Between December 2006 and July 2007, 21 intraoperative pre- and postcryoablation (18-gauge core) biopsies of renal masses were obtained. Evaluation of the biopsies by the institutional uropathologist was followed by a blind assessment by two other uropathologists. Tumor subtype and Fuhrman grade were determined by the three pathologists, while biopsy timing (before or after cryoablation) was only assessed by the two blinded pathologists. The diagnostic yield of the pre- and postcryoablation biopsies and interobserver agreement were calculated. RESULTS: The mean size of the 21 cryoablated tumors was 2.8 cm. No significant bleeding occurred after any biopsy. Of the precryoablation biopsies 75-81% was correctly labeled as precryo, and 48% of the postcryoablation biopsies as postcryo. The diagnostic yield of the three pathologists for precryo biopsies ranged between 67% and 71%, and for postcryo biopsies between 48% and 71% (not statistically different). When combining both types of biopsies, the overall diagnostic yield was 81% for all pathologists. The interobserver agreement was "almost perfect" (kappa = 0.902) for precryo biopsies and "substantial" (kappa = 0.514) for postcryo biopsies. CONCLUSION: This study shows that it is feasible to obtain histopathological diagnoses from postcryoablation biopsies with a diagnostic yield and interobserver agreement similar to precryoablation biopsies.