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Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.
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Sequenciamento do Exoma , Sistema Justaglomerular , Neoplasias Renais , Humanos , Masculino , Feminino , Neoplasias Renais/genética , Neoplasias Renais/patologia , Adulto , Sistema Justaglomerular/patologia , Pessoa de Meia-Idade , Adulto Jovem , Proteínas ras/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Mutação , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , AdolescenteRESUMO
The association between REST reduction and the development of neuroendocrine prostate cancer (NEPC), a novel drug-resistant and lethal variant of castration-resistant prostate cancer (CRPC), is well established. To better understand the mechanisms underlying this process, we aimed to identify REST-repressed long noncoding RNAs (lncRNAs) that promote neuroendocrine differentiation (NED), thus facilitating targeted therapy-induced resistance. In this study, we used data from REST knockdown RNA sequencing combined with siRNA screening to determine that LINC01801 was upregulated and played a crucial role in NED in prostate cancer (PCa). Using The Cancer Genome Atlas (TCGA) prostate adenocarcinoma database and CRPC samples collected in our laboratory, we demonstrated that LINC01801 expression is upregulated in NEPC. Functional experiments revealed that overexpression of LINC01801 had a slight stimulatory effect on the NED of LNCaP cells, while downregulation of LINC01801 significantly inhibited the induction of NED. Mechanistically, LINC01801 is transcriptionally repressed by REST, and transcriptomic analysis revealed that LINC01801 preferentially affects the autophagy pathway. LINC01801 was found to function as a competing endogenous RNA (ceRNA) to regulate the expression of autophagy-related genes by sponging hsa-miR-6889-3p in prostate cancer cells. In conclusion, our data expand the current knowledge of REST-induced NED and highlight the contribution of the REST-LINC01801-hsa-miR-6889-3p axis to autophagic induction, which may provide promising avenues for therapeutic opportunities.
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Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.
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Mesenquimoma , Seios Paranasais , Neoplasias de Tecidos Moles , Humanos , Hibridização in Situ Fluorescente , Fator 1 de Crescimento de Fibroblastos/genética , Neoplasias de Tecidos Moles/genética , Mesenquimoma/genética , Mesenquimoma/patologia , Translocação Genética , Seios Paranasais/patologiaRESUMO
PURPOSE: To compare the diagnostic value of testicular tissue touch print smear (TPS) conducted on azoospermic patients with results obtained from histopathology and in vitro fertility (IVF) lab findings. METHODS: Microdissection testicular sperm extraction was performed on a group of 148 azoospermic patients and testicular samples obtained intraoperatively. Using TPS, the samples were smeared onto a sterile slide, followed with staining using thionine. The testis tissue bulk samples were also transferred to the IVF lab, and determinations of sperm presence or absence obtained from IVF lab tests were compared with the TPS sample results. Needle testis biopsy was separately performed on a group of 360 azoospermic patients, and results of pathohistology review on the biopsies were further compared with determinations of spermatogenesis stage obtained from TPS for those patients. RESULTS: When compared with IVF lab results, TPS was found to have 100% (126/126) positive predictive value and 95.5% (25/26) negative predictive value for predicting sperm presence or absence, respectively. Furthermore, TPS was further found to have a 93.6% correlation (337 of 360 biopsies) with results of histological diagnoses performed by needle biopsy. Results from histology and TPS for the detection of sperm presence were concordant in 96.1% (346/360) of biopsies. Diagnosis of SCO by TPS shows the highest correlation with histopathology (98.6%), followed by complete spermatogenesis (97.5%), early maturation arrest (78.9%), and late maturation arrest (27.3%). CONCLUSIONS: The results support the continued use of TPS in testicular tissue analysis for more rapid assessment of spermatogenesis and for detection of spermatozoa in azoospermic subjects.
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Azoospermia , Oligospermia , Humanos , Masculino , Azoospermia/diagnóstico , Azoospermia/patologia , Oligospermia/patologia , Tato , Sêmen , Espermatozoides/patologia , Testículo/patologia , EspermatogêneseRESUMO
Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I.
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Timoma , Neoplasias do Timo , Fatores de Transcrição TFIII , Fatores de Transcrição TFII , Humanos , Timoma/genética , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias do Timo/genética , Mutação , Fatores de Transcrição TFII/genéticaRESUMO
AIMS: There is strong evidence that cribriform morphology indicates a worse prognosis of prostatic adenocarcinoma. Our aim was to investigate its interobserver reproducibility in prostate needle biopsies. METHODS AND RESULTS: A panel of nine prostate pathology experts from five continents independently reviewed 304 digitised biopsies for cribriform cancer according to recent International Society of Urological Pathology criteria. The biopsies were collected from a series of 702 biopsies that were reviewed by one of the panellists for enrichment of high-grade cancer and potentially cribriform structures. A 2/3 consensus diagnosis of cribriform and noncribriform cancer was reached in 90% (272/304) of the biopsies with a mean kappa value of 0.56 (95% confidence interval 0.52-0.61). The prevalence of consensus cribriform cancers was estimated to 4%, 12%, 21%, and 20% of Gleason scores 7 (3 + 4), 7 (4 + 3), 8, and 9-10, respectively. More than two cribriform structures per level or a largest cribriform mass with ≥9 lumina or a diameter of ≥0.5 mm predicted a consensus diagnosis of cribriform cancer in 88% (70/80), 84% (87/103), and 90% (56/62), respectively, and noncribriform cancer in 3% (2/80), 5% (5/103), and 2% (1/62), respectively (all P < 0.01). CONCLUSION: Cribriform prostate cancer was seen in a minority of needle biopsies with high-grade cancer. Stringent diagnostic criteria enabled the identification of cribriform patterns and the generation of a large set of consensus cases for standardisation.
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Adenocarcinoma , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Reprodutibilidade dos Testes , Biópsia por Agulha , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Biópsia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Gradação de TumoresRESUMO
The classification of malignant tumours is influenced by both immunohistochemical and molecular genetic findings. This is highlighted in the latest World Health Organization classification of renal neoplasia, which has a tumour category of 'tumours that are molecularly defined'. This implies that the defining molecular features are integral to tumourigenesis, which may not necessarily be the case. Renal oncocytoma is recognised as a benign tumour with variable morphology and immunoexpression. A variant of these tumours is hybrid oncocytic chromophobe tumour, which has features of both oncocytoma and chromophobe renal cell carcinoma and may, on rare occasions, show malignant behaviour. Recent reports have proposed two further entities with eosinophilic cytoplasm and varying nuclear pleomorphism, designated low grade oncocytic tumour (LOT) and eosinophilic vacuolated tumour (EVT), formally known as high grade oncocytic tumour (HOT). The diagnosis of these apparently benign tumours was made on the basis of morphological and immunohistochemical features. More recently it has been claimed that the mutations in the mTOR pathway are also a diagnostic feature and it is further suggested that these mutations are key to the pathogenesis of these tumours. As is seen in oncocytoma, immunohistochemical expression of tumours included in series of LOT and EVT is variable. The mutations in the mTOR pathway, where detected, were not constant, with any combination of mTOR, TSC1 and/or TSC2 being involved. A major issue is that in many of the studies full comparative genomic hybridisation results are not presented. In addition it is well recognised that mTOR mutations are seen in a variety of renal tumours. In view of these conflicting results, the rarity of these tumours and their apparent benign nature, raises questions as to why these tumours should be considered specific entities.
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Adenoma Oxífilo , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Adenoma Oxífilo/diagnóstico , Adenoma Oxífilo/genética , Adenoma Oxífilo/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Proliferação de Células , Serina-Treonina Quinases TORRESUMO
Metanephric adenoma (MA) and Wilms tumor (WT) represent 2 prototypes of primary renal neoplasms closely resembling embryonal renal tubules. Tumors with overlapping features may occur, requiring differential diagnoses between the 2. Evidence of divergent oncogenic pathways has been reported, suggesting that MA is driven by BRAF mutation while most WT is of the BRAF wild-type. We collected 4 MA cases, 3 cases of monophasic epithelial WT, and 1 overlap metanephric tumor that contains both conventional MA and high-grade components similar to epithelial WT. Whole-exome sequencing and whole transcriptome sequencing were performed to discover mutations, somatic copy number variation, and differential expression. The findings were compared with those of WT of the TARGET database (WT-TARGET). BRAF V600E mutation was detected in all MAs as well as the overlap tumor but was undetectable in all epithelial WTs and WT-TARGET. The overlap tumor showed an additional pathogenic mutation of SETD2. Three frequent gene mutations observed in WT-TARGET were not common in epithelial WT, in which the mutations appeared sporadic. The profiles of recurrent copy number variations were all different among MA, epithelial WT, and WT-TARGET. Differential expression and unsupervised hierarchical cluster analyses revealed distinct clusters of the 3 categories. Remarkably, the overlap tumor coclustered with MA, separated from epithelial WT and WT-TARGET. The distinctiveness of MA and WT were demonstrated corresponding to BRAF-mutated and non-BRAF-mutated pathways from the molecular perspective. BRAF assay has diagnostic implication for overlap tumors.
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Adenoma , Neoplasias Renais , Tumor de Wilms , Adenoma/genética , Adenoma/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Exoma , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Transcriptoma , Sequenciamento do Exoma , Tumor de Wilms/diagnóstico , Tumor de Wilms/genética , Tumor de Wilms/patologiaAssuntos
Fusão Gênica , Rearranjo Gênico , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Sarcoma/genética , Células Estromais/patologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Sarcoma/patologia , Sequenciamento do ExomaRESUMO
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.
Assuntos
Carcinoma Papilar/patologia , Carcinoma de Células de Transição/patologia , Neoplasias Urológicas/patologia , Humanos , Gradação de Tumores , Urotélio/patologiaRESUMO
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.
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Carcinoma de Células de Transição/patologia , Imunoterapia , Neoplasias Urológicas/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/metabolismo , Humanos , Estadiamento de Neoplasias , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/metabolismoRESUMO
Low-grade endometrial stromal sarcoma and ossifying fibromyxoid tumors are two types of mesenchymal tumors that share no similarities in terms of site, sex, and morphological characteristics. They are rare, low grade tumors of uncertain lineage, with no definite immunological markers. Interestingly, a common PHF1 gene- related rearrangement was observed in these two tumors. Here, we report a case of endometrial stromal sarcoma with distinct ossification. Microscopically, the tumor is composed of bland-looking ovoid cells with low cellularity in the fibromyxoid stroma. Foci of metaplastic bone formation were noted. Using a combination of FISH, transcriptome sequencing, and molecular techniques, we identified a new PHF1-BRD8 fusion transcript, which was previously described, but in its reciprocal fusion form. This case expands the current understanding of low-grade endometrial stromal sarcoma and emphasizes the importance of molecular characterization of unique fusion, which may be related to its distinct morphological features and the possibly chemosensitive target.
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Neoplasias do Endométrio/patologia , Proteínas de Fusão Oncogênica/metabolismo , Osteogênese , Sarcoma/patologia , Sequência de Bases , Neoplasias do Endométrio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas Proto-Oncogênicas c-mdm2/genética , Sarcoma/genética , Coloração e Rotulagem , Células Estromais/patologia , Transcriptoma/genéticaRESUMO
AIMS: Papillary renal neoplasm with reverse polarity (PRNRP) is a newly defined entity with distinct histomorphology and recurrent KRAS mutation. It has been estimated to constitute 4% of previously diagnosed papillary renal cell carcinoma (PRCC). Renal papillary adenoma (PA) is suggested to be the precursor of PRCC. This study aimed to investigate the association between PRNRP and PA, particularly the morphologically similar type D PA. METHODS AND RESULTS: Nephrectomy specimens of PRCC and PA from our 10-year pathology archives were retrieved and reviewed. GATA3 immunohistochemistry and RAS/BRAF testing were performed in all cases reclassified as PRNRP and all PAs with sufficient materials. Overall, PRNRP accounted for 9.1% (10 of 110) of PRCC and there was no recurrence/metastasis with a mean follow-up period of 39 months. Three novel morphological features were described, including clear cell change, mast cell infiltration and metaplastic ossification. Nine of the 10 PRNRPs showed diffuse and strong GATA3 expression and KRAS missense mutations at codon 12. One case exhibited moderate GATA3 staining on 80% of the tumour cells and RAS/BRAF wild-type. In a total of 73 PAs, 11 were classified as type D. GATA3 expression was significantly more frequent in type D versus non-type D PAs (100 versus 35%, P < 0.01). KRAS missense mutations were identified in six of eight (75%) of the type D PAs but none of the 18 non-type D PAs. CONCLUSIONS: Type D PA was different from other types of PA and represented an analogue or a small-sized PRNRP for their identical morphology, immunophenotype and molecular signature.
Assuntos
Adenoma , Carcinoma Papilar , Carcinoma de Células Renais , Neoplasias Renais , Adenoma/diagnóstico , Adenoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/patologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Diagnóstico Diferencial , Feminino , Fator de Transcrição GATA3/análise , Humanos , Imuno-Histoquímica , Rim/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas p21(ras)/análiseRESUMO
Testicular epidermoid cyst (TEC) is an uncommon benign testicular lesion that can be successfully cured via lesion enucleation and at the same time preserving patient's fertility. Doppler ultrasound (US), contrast-enhanced MRI and tumor markers are helpful in the diagnosis of TEC if the lesion does not show typical characteristics such as onion skin and target appearance. Herein, we report a case of TEC without typical structural characteristics but heterogeneously mixed echogenic content in US examination, no internal vascularity in the color Doppler study and lack of contrast enhancement in MRI images. These additional findings are helpful for diagnosing TEC.
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The International Society of Urological Pathology (ISUP) hosts a reference image database supervised by experts with the purpose of establishing an international standard in prostate cancer grading. Here, we aimed to identify areas of grading difficulties and compare the results with those obtained from an artificial intelligence system trained in grading. In a series of 87 needle biopsies of cancers selected to include problematic cases, experts failed to reach a 2/3 consensus in 41.4% (36/87). Among consensus and non-consensus cases, the weighted kappa was 0.77 (range 0.68-0.84) and 0.50 (range 0.40-0.57), respectively. Among the non-consensus cases, four main causes of disagreement were identified: the distinction between Gleason score 3 + 3 with tangential cutting artifacts vs. Gleason score 3 + 4 with poorly formed or fused glands (13 cases), Gleason score 3 + 4 vs. 4 + 3 (7 cases), Gleason score 4 + 3 vs. 4 + 4 (8 cases) and the identification of a small component of Gleason pattern 5 (6 cases). The AI system obtained a weighted kappa value of 0.53 among the non-consensus cases, placing it as the observer with the sixth best reproducibility out of a total of 24. AI may serve as a decision support and decrease inter-observer variability by its ability to make consistent decisions. The grading of these cancer patterns that best predicts outcome and guides treatment warrants further clinical and genetic studies. Results of such investigations should be used to improve calibration of AI systems.
Assuntos
Inteligência Artificial , Interpretação de Imagem Assistida por Computador/métodos , Gradação de Tumores/métodos , Gradação de Tumores/normas , Neoplasias da Próstata/patologia , Bases de Dados Factuais , Humanos , Interpretação de Imagem Assistida por Computador/normas , Masculino , Variações Dependentes do ObservadorRESUMO
Foci of necrosis are frequently seen in malignant tumours and may be due to a variety of causes. Different types of necrosis are given various names based upon their morphological features and presumed pathogenesis, such as coagulative, liquefactive and fibrinoid necrosis. Here, we propose the term 'granular necrosis' (GN) for a specific form of tumour necrosis characterised by the presence of well-defined necrotic foci being sharply demarcated from adjacent viable tumour. A constant feature is loss of architecture resulting in an amorphous necrotic mass containing granular nuclear and cytoplasmic debris, without an associated neutrophilic infiltrate. There is usually extensive karyorrhexis, which in larger tumours is more prominent at the periphery. These foci are often microscopic but may range up to several millimetres or larger in size. This distinctive form of necrosis has been erroneously given a variety of names in the literature including coagulative necrosis and microscopic necrosis, which on the basis of the aforementioned gross and microscopic findings is inappropriate. It is apparent that this is a specific form of necrosis, hence the descriptive term 'granular necrosis' that differentiates this form of necrosis from other types. The presence of GN is recognised as occurring in a variety of tumour types, being commonly seen in renal cell carcinoma, where it has been shown to have independent prognostic significance. In some epithelial and stromal tumours of the uterus, the presence of GN also has prognostic significance and is a defining feature for the differentiation of uterine leiomyoma and leiomyosarcoma. The pathogenesis of GN is unresolved. It does not show the features of apoptosis and in recent studies has been shown to have some of the molecular changes associated with necroptosis.
Assuntos
Morte Celular/fisiologia , Necrose/patologia , Neoplasias/patologia , HumanosRESUMO
ALK rearranged renal cell carcinoma (ALK-RCC) has recently been included in 2016 WHO classification as a provisional entity. In this study, we describe 12 ALK-RCCs from 8 institutions, with detailed clinical, pathological, immunohistochemical (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) analyses. Patients' age ranged from 25 to 68 years (mean, 46.3 years). Seven patients were females and five were males (M:F = 1:1.4). Tumor size ranged from 17 to 70 mm (mean 31.5, median 25 mm). The pTNM stage included: pT1a (n = 7), pT1b (n = 1), and pT3a (n = 4). Follow-up was available for 9/12 patients (range: 2 to 153 months; mean 37.6 months); 8 patients were alive without disease and one was alive with distant metastases. The tumors demonstrated heterogeneous, 'difficult to classify' morphology in 10/12 cases, typically showing diverse architectural and cellular morphologies, including papillary, tubular, tubulocystic, solid, sarcomatoid (spindle cell), rhabdoid, signet-ring cell, and intracytoplasmic vacuoles, often set in a mucinous background. Of the remaining two tumors, one showed morphology resembling mucinous tubular and spindle cell renal cell carcinoma (MTSC RCC-like) and one was indistinguishable from metanephric adenoma. One additional case also showed a focal metanephric adenoma-like area, in an otherwise heterogeneous tumor. By IHC, all tumors were diffusely positive for ALK and PAX8. In both cases with metanephric adenoma-like features, WT1 and ALK were coexpressed. ALK rearrangement was identified in 9/11 tumors by FISH. ALK fusion partners were identified by NGS in all 12 cases, including the previously reported: STRN (n = 3), TPM3 (n = 3), EML4 (n = 2), and PLEKHA7 (n = 1), and also three novel fusion partners: CLIP1 (n = 1), KIF5B (n = 1), and KIAA1217 (n = 1). ALK-RCC represents a genetically distinct entity showing a heterogeneous histomorphology, expanded herein to include unreported metanephric adenoma-like and MTSC RCC-like variants. We advocate a routine ALK IHC screening for "unclassifiable RCCs" with heterogeneous features.
Assuntos
Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Fusão Gênica , Rearranjo Gênico , Neoplasias Renais/genética , Cinesinas/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas/genética , Adulto , Idoso , Ásia , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/secundário , Europa (Continente) , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , América do Norte , Estudos RetrospectivosRESUMO
AIMS: The Cancer Genome Atlas (TCGA) provides an integrated resource for investigating the genetic, phenotypical and clinical characteristics of cancer. In this study, we aimed to define distinct subsets of clear cell renal cell carcinoma (ccRCC) through differential expression and principal component analyses. METHODS AND RESULTS: We used DESeq2 to examine the expression profiles of 472 cases in TCGA. After a process of segregation and regrouping, we compared the mutation and copy number variation landscapes to discern two major clusters: cluster 1, composed mainly of classic ccRCC, and cluster 2, which was associated with gains at chromosomes 7 and 12. Gene set enrichment analysis disclosed that cluster 2 tumours were enriched in genes involving epithelial-mesenchymal transition. Histologically, cluster 2 tumours frequently exhibited cell elongation or spindling. Patients with cluster 2 tumours or tumours harbouring chromosomes 7 or 12 gains had a significantly greater cumulative incidence of mortality. We then employed fluorescence in-situ hybridisation with probes against chromosomes 7 and 12 in a cohort of 119 cases of ccRCC from our institute for validation. Chromosomes 7 and 12 gains were associated with lower survival rates in both univariate and multivariate analyses. CONCLUSIONS: Our study demonstrates that genetic data obtained through appropriate molecular methodologies can be a useful adjunct to help predict prognosis. It also provides an example of exploring TCGA to extract meaningful information that can eventually contribute to precision medicine.
Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 7/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , MasculinoRESUMO
BACKGROUND: An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading. METHODS: We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50-69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa. FINDINGS: The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994-0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972-0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95-0·97) for the independent test dataset and 0·87 (0·84-0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60-0·73). INTERPRETATION: An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist. FUNDING: Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.