RESUMO
Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Neuroepiteliomatosas , Humanos , Adulto Jovem , Biomarcadores Tumorais/genética , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fusão Gênica , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Receptores Proteína Tirosina Quinases/genética , Proteína Nuclear Ligada ao X/genéticaRESUMO
Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2-8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3-19 months.
Assuntos
Neoplasias Pulmonares , Humanos , Crizotinibe/uso terapêutico , Receptores ErbB/genética , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-met/genética , /farmacologiaRESUMO
Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch-repair deficiency (CMMRD), caused by germline bi-allelic PVs affecting one of four MMR genes, results in a high propensity for the hematological, brain, intestinal tract, and other malignancies in childhood. Nonmalignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD-like patients, have not previously been reported as germline PVs despite all being well-known somatic mutations in hyper-mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger "mutator" effect than known PPAP-associated POLE PVs and may cause a CMMRD-like phenotype distinct from PPAP. The common underlying mechanism, that is, a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD.
Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Adulto , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , FenótipoRESUMO
Anaplastic lymphoma-kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is prone to developing heterogeneous, only partly known mechanisms of resistance to ALK-tyrosine-kinase-inhibitors (ALK-TKIs). We present a case of a 38-year old male, who never smoked with disseminated ALK-rearranged (EML4 (20) - ALK (20) fusion variant 2) lung adenocarcinoma, who received four sequentially different ALK-TKIs and two lines of chemotherapy in-between. We observed significant clinical benefit by the first three ALK-TKIs (Crizotinib, Ceritinib, Alectinib) and chemotherapy with Pemetrexed, resulting in overall survival over 3 years. Longitudinal assessment of progressions by rebiopsies from hepatic metastases showed different mechanisms of resistance to each ALK-TKI, including secondary ALK-mutations and the downstream p.V600E BRAF-mutation that had not been linked to second-generation ALK-TKIs before. Ultimately, in connection with terminal rapid progression and resistance to Alectinib and Lorlatinib, we identified phenotypical epithelial-mesenchymal transition (EMT) of newly occurred metastatic cells, a phenomenon not previously related to these two ALK-TKIs. This resistance heterogeneity suggests a continuously changing disease state. Sequential use of different generation's ALK-TKIs and combination therapies may yield prolonged responses with satisfactory quality of life in patients with advanced ALK-positive NSCLC. However, the development of EMT is a major hurdle and may explain rapid disease progression and lack of response to continued ALK-inhibition.
Assuntos
Quinase do Linfoma Anaplásico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Rearranjo Gênico , Inibidores de Proteínas Quinases/farmacologia , Adulto , Quinase do Linfoma Anaplásico/metabolismo , Biópsia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Imuno-Histoquímica , Masculino , Mutação , Proteínas de Fusão Oncogênica/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Neuroinflammation is an essential part of neurodegeneration. Yet, the current understanding of neuroinflammation-associated molecular events in distinct brain regions of prion disease patients is insufficient to lay the ground for effective treatment strategies targeting this complex neuropathological process. To address this problem, we analyzed the expression of 800 neuroinflammation-associated genes to create a profile of biological processes taking place in the frontal cortex and cerebellum of patients who suffered from sporadic Creutzfeldt-Jakob disease. The analysis was performed using NanoString nCounter technology with human neuroinflammation panel+. The observed gene expression patterns were regionally and sub-regionally distinct, suggesting a variable neuroinflammatory response. Interestingly, the observed differences could not be explained by the molecular subtypes of sporadic Creutzfeldt-Jakob disease. Furthermore, analyses of canonical pathways and upstream regulators based on differentially expressed genes indicated an overlap between biological processes taking place in different brain regions. This suggests that even smaller-scale spatial data reflecting subtle changes in brain cells' functional heterogeneity and their immediate pathologic microenvironments are needed to explain the observed differential gene expression in a greater detail.
Assuntos
Biomarcadores , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/etiologia , Síndrome de Creutzfeldt-Jakob/metabolismo , Expressão Gênica , Idoso , Encéfalo/patologia , Microambiente Celular/genética , Microambiente Celular/imunologia , Biologia Computacional/métodos , Síndrome de Creutzfeldt-Jakob/patologia , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , TranscriptomaRESUMO
AIMS: Interpretation of cytology samples from pancreatic cysts is challenging. A novel microbiopsy forceps used during endoscopic ultrasound examinations offers new opportunities for histological examination of tissue from pancreatic cysts as well as next-generation sequencing. The aim of this study was to analyse the results of next-generation sequencing of microbiopsies from pancreatic cysts. METHODS AND RESULTS: Microbiopsies from 27 patients were obtained, 23 of which were subjected to next-generation sequencing. Sixteen intraductal papillary mucinous neoplasms harboured mutations in genes regulating cell cycle and repair, and three were without mutations. Most frequent mutations were found in the KRAS and GNAS genes, and these were often concomitant. Three serous cystic neoplasms were without mutations, while with regard to histology, a non-diagnostic microbiopsy harboured a KRAS and a TP53 mutation and was deemed malignant after clinical follow-up. Three patients underwent surgery, and the point mutations detected in the microbiopsies were confirmed in the resected specimens. We identified one resected sample with an additional GNAS mutation which was not identified in the microbiopsy. CONCLUSIONS: Next-generation sequencing of microbiopsies may have the potential to improve diagnostic decision-making.
Assuntos
Biomarcadores Tumorais/genética , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Cisto Pancreático , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Cromograninas/genética , Análise Mutacional de DNA , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Genes p53 , Humanos , Masculino , Pessoa de Meia-Idade , Cisto Pancreático/diagnóstico , Cisto Pancreático/genética , Cisto Pancreático/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
ABSTRACT: Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient-tailored treatment. To investigate associated mechanisms, we analyzed clinical data and used immunohistochemistry, gene-expression profiling, cytogenetics, and next-generation sequencing in a cohort of 117 patients with PSDLBCL. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression-free survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (5-year PFS: ABC, 43% vs GCB, 73%; LSM: ABC, 45% vs GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5-year PFS: ABC, 55% vs GCB, 85%; LSM: ABC, 28% vs GCB, 0%). ABC lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (P < .01). The ABC subtype frequently displayed cMYC/BCL2 coexpression (76% vs 18% GCB; P < .001) and HLA-II loss (48% vs 10% GCB; P < .001). PD-L1 expression and copy-number alterations were rare. All lymphomas were Epstein-Barr virus-negative. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known relapse/dissemination sites. The ABC subgroup's MCD genetic features, shared with lymphomas at other nonprofessional lymphoid sites, make them potential candidates for targeted B-cell and toll-like receptor signaling therapy.
Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Humanos , Fator 88 de Diferenciação Mieloide/metabolismo , Herpesvirus Humano 4/metabolismo , Recidiva Local de Neoplasia , Prognóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , RecidivaRESUMO
OBJECTIVE: Meningioma is the most common primary intracranial neoplasm. Only 1%-3% of meningiomas are malignant according to the 2016 WHO criteria (WHO grade III). High-grade meningiomas present specific gene expression signatures indicating aggressive growth or recurrence. However, changes in gene expression and in neuroinflammatory gene expression signatures in WHO grade III meningiomas and during progression from WHO grade I or II to grade III are unknown. METHODS: The authors used a NanoString targeted gene expression panel with focus on 787 genes relevant in meningioma pathology and neuroinflammatory pathways to investigate patients with grade III meningiomas treated at Rigshospitalet from 2000 to 2020 (n = 51). A temporal dimension was added to the investigation by including samples from patients' earlier grade I and II meningiomas and grade III recurrences (n = 139 meningiomas). The authors investigated changes in neuroinflammatory gene expression signatures in 1) grade I meningiomas that later transformed into grade III meningiomas, and 2) grade III meningiomas compared with nonrecurrent grade I meningiomas. RESULTS: The authors' data indicate that FOXM1, TOP2A, BIRC5, and MYBL2 were enriched and the HOTAIR regulatory pathway was enriched in grade III meningiomas compared with nonrecurrent grade I meningiomas. They discovered a separation of malignant and benign meningiomas based only on genes involved in microglia regulation with enrichment of P2RY12 in grade I compared with grade III meningiomas. Interestingly, FOXM1 was upregulated in premalignant grade I meningioma years before the grade III transformation. CONCLUSIONS: The authors found gene expression changes in low-grade meningiomas that predated histological transformation to grade III meningiomas. Neuroinflammation genes distinguished grade III from grade I meningiomas.
Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/patologia , Neoplasias Meníngeas/patologia , Perfilação da Expressão Gênica , Recidiva Local de Neoplasia/patologiaRESUMO
AIMS: Though formalin remains to be the gold standard fixative in pathology departments, analytical challenges persist for nucleic acid evaluations. In our laboratory, formalin fixation of skin samples in particular impairs diagnostic accuracy and demands repetition of biopsies and analytical procedures. PAXgene Tissue Systems may be an alternative; however, according to manufacturer specifications it only allows fixation for 48 hours before having to add a stabiliser. This may be a challenge in laboratories, which are closed in weekends and bank holidays. Our aim was to validate this alternative fixative for dermatological samples with prolonged fixation times using standard laboratory protocols developed for formalin-fixed specimens. We compared the results with gold standard formalin fixation. METHODS: Skin specimens were formalin or PAXgene fixed for either 2 hours, 24 hours, 3 days or 7 days, paraffin-embedded, analysed and scored by observers. RESULTS: Generally, formalin outperformed PAXgene fixation in H&E stains and fluorescence in situ hybridisation (FISH), but both seem usable for diagnostics. Time of PAXgene fixation did not have an impact on alcian blue-Van Gieson (ABVG), H&E (p=0.48), nor immunohistochemistry (p=0.74). There was a tendency towards best PAXgene performance at 24 hours of fixation for FISH, and for DNA integrity analysis 24 hours or 3 days. CONCLUSIONS: Prolonging PAXgene fixation time to 3 days before adding stabiliser does not seem to have major impact on performance of general diagnostic analysis, but our preliminary results show optimisation of internal protocols are needed. PAXgene is an expensive alternative and may be confined to some dermatological samples.
Assuntos
Fatores de Transcrição Box Pareados/metabolismo , Manejo de Espécimes/métodos , Fixação de Tecidos/métodos , Mama/metabolismo , Dermatologia , Feminino , Fixadores , Formaldeído , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Laboratórios , Fatores de Transcrição Box Pareados/genética , Tonsila Palatina/metabolismo , Inclusão em Parafina , Pele/metabolismo , Coloração e RotulagemRESUMO
The purpose of this study was to perform an updated reclassification of all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over the past 40 years, putting a special emphasis on the molecular characterization of novel disease subtypes. Investigation of the Danish prion diseases cohort revealed rare sporadic Creutzfeldt-Jakob disease cases with mixed subtypes and subtypes with previously uncharacterized white matter plaques, a new case of sporadic fatal insomnia, and 3 novel mutations, including 2 large octapeptide repeat insertions, and a point mutation in the prion protein gene. The evaluation of methionine and valine distribution at codon 129 among the prion disease patients in the cohort revealed the increased prevalence of methionine homozygotes compared to the general population. This observation was in line with the prevalence reported in other Caucasian prion disease cohort studies. Reclassification of the old prion diseases cohort revealed unique cases, the molecular characterization of which improves prion diseases classification, diagnostic accuracy, genetic counseling of affected families, and the understanding of disease biology.
Assuntos
Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/genética , Doenças Priônicas/genética , Doenças Priônicas/patologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Estudos de Coortes , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Priônicas/diagnóstico , Doenças Priônicas/metabolismo , Substância Branca/metabolismo , Substância Branca/patologiaRESUMO
Until recently, diagnostics of brain tumors were almost solely based on morphology and immunohistochemical stainings for relatively unspecific lineage markers. Although certain molecular markers have been known for longer than a decade (combined loss of chromosome 1p and 19q in oligodendrogliomas), molecular biomarkers were not included in the WHO scheme until 2016. Now, the classification of diffuse gliomas rests on an integration of morphology and molecular results. Also, for many other central nervous system tumor entities, specific diagnostic, prognostic and predictive biomarkers have been detected and continue to emerge. Previously, we considered brain tumors with similar histology to represent a single disease entity. We now realize that histologically identical tumors might show alterations in different molecular pathways, and often represent separate diseases with different natural history and response to treatment. Hence, knowledge about specific biomarkers is of great importance for individualized treatment and follow-up. In this paper we review the biomarkers that we currently use in the diagnostic work-up of brain tumors.
Assuntos
Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/genética , Ependimoma/diagnóstico , Ependimoma/genética , Glioma/diagnóstico , Glioma/genética , Humanos , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Meningioma/diagnóstico , Meningioma/genética , Mutação , Oligodendroglioma/diagnóstico , Oligodendroglioma/genética , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genéticaRESUMO
Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20-30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.
RESUMO
The spectrum of tumors arising in the salivary glands is wide and has recently been shown to harbor a network of tumor-specific fusion genes. Acinic cell carcinoma (AciCC) is one of the more frequently encountered types of salivary gland carcinoma, but it has remained a genetic orphan until recently when a fusion between the HTN3 and MSANTD3 genes was described in one case. Neither of these 2 genes is known to be implicated in any other malignancy. This study was undertaken to investigate whether the HTN3-MSANTD3 fusion is a recurrent genetic event in AciCC and whether it is a characteristic of one of its histological variants. Of the 273 AciCCs screened, 9 cases showed rearrangement of MSANTD3 by break-apart fluorescence in situ hybridization, 2 had 1 to 2 extra signals, and 1 had gain, giving a total of 4.4% with MSANTD3 aberrations. In 6 of 7 available cases with MSANTD3 rearrangement, the HTN3-MSANTD3 fusion transcript was demonstrated with real-time polymerase chain reaction. Histologically, all fusion-positive cases were predominantly composed of serous tumor cells growing in solid sheets, with serous tumor cells expressing DOG-1 and the intercalated duct-like cell component being CK7 positive and S-100 positive in 6/9 cases. All but one case arose in the parotid gland, and none of the patients experienced a recurrence during follow-up. In contrast, the case with MSANTD3 gain metastasized to the cervical lymph nodes and lungs. In conclusion, we find the HTN3-MSANTD3 gene fusion to be a recurrent event in AciCC with prominent serous differentiation and an indolent clinical course.
Assuntos
Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patologia , Proteínas de Ligação a DNA/genética , Histatinas/genética , Fusão Oncogênica , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Secretory carcinoma has been described in the breast, salivary glands, skin, and other organs, but has not been reported in the lacrimal gland to date. Since lacrimal and salivary glands show similar tumors, we hypothesized that lacrimal secretory carcinoma may exist but has been misclassified in the past. DESIGN: We undertook a retrospective review of all lacrimal gland tumors at 2 tertiary institutions with centralized ocular pathology practices. METHODS: A total of 350 lacrimal tumors were reviewed by the authors. Candidate tumors were tested for ETV-NTRK rearrangement by fluorescence in situ hybridization and the presence of the translocation was confirmed by next-generation sequencing. RESULTS: We identified a single case of secretory carcinoma. The diagnosis was confirmed by demonstrating specific immunohistochemical profile and the presence of ETV6-NTRK3 gene fusion, which is characteristic of secretory carcinoma of other sites. The tumor occurred in a young man who was treated with surgery alone with no recurrence during 12 years of follow-up. CONCLUSION: Secretory carcinoma is a new lacrimal gland carcinoma type that should be added to the spectrum of low-grade lacrimal gland tumors.
Assuntos
Carcinoma/diagnóstico , Neoplasias Oculares/diagnóstico , Doenças do Aparelho Lacrimal/diagnóstico , Adulto , Biomarcadores Tumorais/genética , Carcinoma/genética , Carcinoma/cirurgia , Neoplasias Oculares/genética , Neoplasias Oculares/cirurgia , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Doenças do Aparelho Lacrimal/genética , Doenças do Aparelho Lacrimal/cirurgia , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Patients with epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer (NSCLC) obtain substantial clinical benefit from EGFR tyrosine-kinase inhibitors (TKIs), but will ultimately develop TKI-resistance resulting in median progression-free survival of 9-15 months during first-line TKI-therapy. However, type and timing of TKI-resistance cannot be predicted and several mechanisms may simultaneously/subsequently occur during TKI-treatment. In this respect, we present a 49 year-old Caucasian male ex-smoker with metastatic pulmonary adenocarcinoma (ADC) that concomitantly harbored an EGFR exon 19-mutation (p.E746_A750delELREA) and a previously unreported 2bp frame-shift microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. Interestingly, FGFR3-mutations have previously been described in other cancer types of Caucasian patients and may represent an alternative pathway to EGFR-signaling. The patient received first-line erlotinib but after only 7 weeks showed metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) that retained the EGFR- and FGFR3-mutations was identified. Consequently, standard carboplatin-etoposide regimen for SCLC combined with erlotinib continuation was implemented obtaining significant objective response. However, after completing 6 cycles of this combination, new pulmonary and hepatic metastases appeared and showed persistence of the original EGFR- and FGFR3-mutated ADC phenotype together with acquisition of the erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased. Thus, this advanced EGFR-mutated NSCLC displayed very rapid onset and heterogeneous genetic and phenotypic mechanisms of TKI-resistance occurring at different times and locations of metastatic disease: concomitant FGFR3-mutation before and during TKI-treatment as potential intrinsic mechanism for the rapid progression; transformation to SCLC at first progression during TKI-therapy; acquired T790M EGFR-mutation at second progression. Our case also underlines that, when achievable, rebiopsies of progressive sites during TKI-treatment are important for identifying heterogeneous histopathological and molecular resistance mechanisms and better defining possible treatment modifications.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Antineoplásicos/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Cloridrato de Erlotinib/administração & dosagem , Etoposídeo/administração & dosagem , Éxons/genética , Heterogeneidade Genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genéticaAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina , Anquirinas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-ret , Pirazóis , Piridinas , PirimidinasRESUMO
Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Rearranjo Gênico , Neoplasias dos Seios Paranasais/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Adenocarcinoma/química , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biópsia , Feminino , Fusão Gênica , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Imageamento por Ressonância Magnética , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia , Neoplasias dos Seios Paranasais/química , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/cirurgia , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Receptor trkC/genética , Resultado do Tratamento , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
BACKGROUND: Anaplastic lymphoma kinase-positive non-small cell lung carcinoma patients are generally highly responsive to the dual anaplastic lymphoma kinase and MET tyrosine kinase inhibitor crizotinib. However, they eventually acquire resistance to this drug, preventing the anaplastic lymphoma kinase inhibitors from having a prolonged beneficial effect. The molecular mechanisms responsible for crizotinib resistance are beginning to emerge, e.g., in some anaplastic lymphoma kinase-positive non-small cell lung carcinomas the development of secondary mutations in this gene has been described. However, the events behind crizotinib-resistance currently remain largely uncharacterized. Thus, we report on an anaplastic lymphoma kinase-positive non-small cell lung carcinoma patient with concomitant occurrence of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations upon development of crizotinib-resistance. CASE PRESENTATION: A 61-year-old Caucasian never-smoking male was diagnosed with anaplastic lymphoma kinase -positive pulmonary adenocarcinoma, stage T4N3M1b. Treatment with crizotinib initially resulted in complete objective response in the thorax and partial response in the abdomen, but after 8 months of therapy the patient acquired resistance and progressed. Biopsies from new metastases revealed development of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations concomitant with the original anaplastic lymphoma kinase gene rearrangement and without signs of anaplastic lymphoma kinase fusion gene amplification or secondary anaplastic lymphoma kinase mutations. CONCLUSION: To our knowledge, this is the first report of an anaplastic lymphoma kinase-positive pulmonary adenocarcinoma, which upon emergence of crizotinib resistance acquired 2 new somatic mutations in the epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog genes, respectively, concomitant with the original anaplastic lymphoma kinase rearrangement. Thus, these 3 driver mutations, usually considered mutually exclusive, may coexist in advanced non-small cell lung carcinoma that becomes resistant to crizotinib, presumably because heterogeneous tumor clones utilize epidermal growth factor receptor and/or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog signaling to circumvent the inhibition of anaplastic lymphoma kinase-mediated signaling by crizotinib. The identification of new targetable somatic mutations by tumor re-biopsy may help clarify the mechanism behind the development of the acquired crizotinib resistance and pave the way for combined strategies involving multiple targeted therapies.