RESUMO
Mutations affecting codon 172 of the isocitrate dehydrogenase 2 (IDH2) gene define a subgroup of sinonasal undifferentiated carcinomas (SNUCs) with a relatively favorable prognosis and a globally hypermethylated phenotype. They are also recurrent (along with IDH1 mutations) in gliomas, acute myeloid leukemia, and intrahepatic cholangiocarcinoma. Commonly reported mutations, all associated with aberrant IDH2 enzymatic activity, include R172K, R172S, R172T, R172G, and R172M. We present a case of SNUC with a never-before-described IDH2 mutation, R172A. Our report compares the methylation pattern of our sample to other cases from the Gene Expression Omnibus database. Hierarchical clustering suggests a strong association between our sample and other IDH-mutant SNUCs and a clear distinction between sinonasal normal tissues and tumors. Principal component analysis (PCA), using 100 principal components explaining 94.5% of the variance, showed the position of our sample to be within 1.02 standard deviation of the other IDH-mutant SNUCs. A molecular modeling analysis of the IDH2 R172A versus other R172 variants provides a structural explanation to how they affect the protein active site. Our findings thus suggest that the R172A mutation in IDH2 confers a gain of function similar to other R172 mutations in IDH2, resulting in a similar hypermethylated profile.
Assuntos
Carcinoma , Metilação de DNA , Isocitrato Desidrogenase , Neoplasias do Seio Maxilar , Mutação , Humanos , Isocitrato Desidrogenase/genética , Metilação de DNA/genética , Carcinoma/genética , Carcinoma/patologia , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Masculino , Pessoa de Meia-Idade , Feminino , IdosoRESUMO
The objective of this study was to report outcomes for 19 consecutive patients with SMARCB1 (INI-1)-deficient sinonasal carcinoma. Patients were treated from 2014 to 2021 and followed for a median of 22.3 months. The median overall survival (OS) and disease-free survival (DFS) were 31.8 and 9.9 months, respectively. Patients with nasal cavity or maxillary sinus tumors had 84% better disease-specific survival (DSS) (hazard ratio [HR], 0.136; 95% confidence interval [CI], 0.028-0.66; p = .005) and 71% better DFS (HR, 0.29; 95% CI, 0.097-0.84; p = .041) than patients with other sinonasal sites. Patients who received induction chemotherapy were 76% less likely to die of disease (DSS HR, 0.241; 95% CI, 0.058-1.00; p = .047). In the largest single-institution study of SMARCB1-deficient sinonasal carcinoma to date, OS and DFS approached 3 years and 1 year, respectively, but were better for nasal cavity and maxillary sinus tumors. Patients may benefit from induction chemotherapy.
Assuntos
Carcinoma , Neoplasias do Seio Maxilar , Neoplasias dos Seios Paranasais , Humanos , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/terapia , Neoplasias do Seio Maxilar/patologia , Neoplasias dos Seios Paranasais/genética , Neoplasias dos Seios Paranasais/terapia , Neoplasias dos Seios Paranasais/patologia , Carcinoma/genética , Carcinoma/terapia , Carcinoma/patologia , Proteína SMARCB1/genéticaRESUMO
SMARCB1 deficient sinonasal carcinomas are rare neoplasms, classified under sinonasal undifferentiated carcinomas by the fourth edition of the World Health Organization (WHO) classification of head and neck tumors. It is characterized immunohistochemically by loss of SMARCB1(INI1) expression. We are reporting the case of a 63-year-old man who was evaluated for nasal stuffiness of 3 months duration in another hospital where a radiological evaluation showed a polypoidal soft tissue lesion in the right maxillary sinus extending to the right nasal cavity and spheno-ethmoidal sinus. He underwent excision biopsy which was reported as non- keratinizing nasopharyngeal carcinoma. He was referred to our center with residual disease in spheno-ethmoidal recess for which radiotherapy was given. After completion of radiotherapy, the primary site had no residual disease, but while on follow-up he developed left sided neck nodes within 4 months of completion of treatment. Excision of the lesion was done and histopathological and immunohistochemical analysis revealed it to be metastasis from SMARCB1 deficient sinonasal carcinoma and not nasopharyngeal carcinoma as diagnosed from the other center. This case is being reported to highlight the diagnostic challenge associated with this rare entity.
Assuntos
Carcinoma , Neoplasias do Seio Maxilar , Neoplasias Nasofaríngeas , Masculino , Humanos , Pessoa de Meia-Idade , Proteína SMARCB1/genética , Proteína SMARCB1/análise , Neoplasias do Seio Maxilar/diagnóstico , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/metabolismo , Carcinoma/diagnóstico , Carcinoma/genética , Carcinoma/metabolismo , Biópsia , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análiseRESUMO
The classification of poorly differentiated sinonasal carcinomas and their nonepithelial mimics has experienced tremendous developments during the last 2 decades. These recent developments paved the way for an increasingly adopted approach to a molecular-based or etiology-based refined classification of the many carcinoma variants that have been historically lumped into the sinonasal undifferentiated carcinoma category. Among these new achievements, recognition of carcinoma subtypes driven by defects in the Switch/Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex represents a major highlight. This resulted in a new definition of 4 sinonasal entities driven solely or predominantly by Switch/Sucrose nonfermentable complex deficiency: (1) SMARCB1(INI1)-deficient sinonasal carcinoma (lacking gland formation and frequently displaying a non-descript basaloid, and less frequently eosinophilic/oncocytoid morphology, but no features of other definable subtypes), (2) SMARCB1-deficient sinonasal adenocarcinoma (with unequivocal glands or yolk sac-like pattern), (3) SMARCA4-deficient undifferentiated (sinonasal undifferentiated carcinoma-like) carcinoma (lacking glandular or squamous immunophenotypes), and (4) SMARCA4-deficient subset (~80%) of sinonasal teratocarcinosarcoma. Fortunately, diagnostic loss of all these proteins can be detected by routine immunohistochemistry, so that genetic testing is not mandatory in routine practice. This review summarizes the main demographic, clinicopathological, and molecular features of these new entities.
Assuntos
Adenocarcinoma , Carcinoma , Neoplasias do Seio Maxilar , Neoplasias Nasais , Humanos , Carcinoma/patologia , Neoplasias do Seio Maxilar/genética , Proteína SMARCB1/genética , Biomarcadores Tumorais/genética , DNA Helicases , Proteínas Nucleares , Fatores de Transcrição/genéticaRESUMO
INTRODUCTION: Genetic profiling has caused an explosion in the subclassification of sinonasal malignancies. Distinguishing several of these tumor types by histomorphology alone has been quite challenging, and although pathologic classification aims to be as specific as possible, it remains to be seen if this recent move toward tumor speciation bears clinical relevance, most particularly focused on subtyping for the sake of prognostication and treatment. One such recently described cohort, predominantly lumped under the moniker of sinonasal undifferentiated carcinoma (SNUC) is IDH2 -mutated sinonasal carcinoma, a high-grade carcinoma associated with mutations in the isocitrate dehydrogenase-2 ( IDH2 ) gene. A hotspot mutation in the R172 codon has been described in 50% to 80% of the tumors classified as SNUC, large cell neuroendocrine carcinomas, and rarely in cases classified as olfactory neuroblastoma. The use of immunohistochemical and molecular approaches is required to correctly identify this subset of sinonasal tumors, with further study necessary to elucidate their unique pathophysiology, ultimately determining whether a revision is required toward the current therapeutic approach. AIMS: Here, we provide an overview of the IDH2- mutated sinonasal tumors, discuss histopathologic and clinical features, and focus on molecular diagnostics and novel immunohistochemical markers. RESULTS: A review of the literature reveals 82 reported cases with IDH2 -mutated sinonasal tumors (IST), confirmed either by molecular studies or diagnostic immunohistochemical markers. The mean patient age is 60 years (female/male: 1/1.4), the median tumor size is 5 cm (range: 2.5 to 7.0 cm), and the most common location is the nasal cavity (81%). IST displays tumor necrosis and increased mitotes. Histopathologically, IST shows SNUC-like, large cell neuroendocrine carcinomas-like, or poorly differentiated carcinoma-like features (77%, 12%, and 9%, respectively). The molecular hotspot alterations in mitochondrial IDH2 are: R172S (61%), R172T (19%), R172G (7%), and R172M (3%). Sixty-five percent of tumors are surgically resectable, and all patients received chemotherapy, radiation therapy, or both. Rates of locoregional recurrence and distant metastasis are 60% and 40%, respectively. One-, 3- and 5-year survival rates are 83%, 50%, and 43%, respectively. In all but 1 study, IST is associated with better outcomes than IDH2 wild-type tumors and SMARCB1 -deficient sinonasal tumors.
Assuntos
Carcinoma Neuroendócrino , Neoplasias do Seio Maxilar , Neoplasias Epiteliais e Glandulares , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Mutação , Biomarcadores Tumorais/genéticaRESUMO
INTRODUCTION: The sinonasal carcinoma are rare tumors of the head and neck. The undifferentiated sinonasal carcinoma subtypes are constantly being explored and new mutations, with different prognosis markers and biological behaviors are being described. The SMARCB1 negative sinonasal carcinoma subtypes have been recently described with few reports of leptomeningeal and spinal cord invasion. CASE PRESENTATION: This study presents the case of a 59-year-old woman, with no previous disease, presenting initially with epistaxis that evolved to cranial nerve deficits and a left eye complete oftalmoplegia. After diagnostic investigation, she had a diagnosis of a left ethmoid sinus sinonasal carcinoma. Following resection of the tumor, she evolved with a right foot drop that eventually has been linked to diffuse spinal cord impairment. The histopathological diagnosis confirmed a SMARCB1 negative sinonasal carcinoma. Due to the diffuse metastasis, she underwent palliative care and died eight months after the surgery. DISCUSSION: Spinal cord metastasis may manifest with different clinical signs. Our case shows a rare manifestation of SMARCB1-deficient sinonasal carcinoma, a new subtype of sinonasal carcinoma, summarizing the importance of a high grade of suspicion of spinal cord invasion on these patients. SMARCB1 sinonasal carcinomas are rare new tumors of the head and neck, whose biological behaviors are yet to be explored. To the best of our knowledge, this is one of the few case reports describing simultaneous spread of this tumor to the central nervous system and spinal cord.
Assuntos
Neoplasias do Seio Maxilar , Neuropatias Fibulares , Neoplasias da Medula Espinal , Biomarcadores Tumorais/genética , Feminino , Humanos , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Pessoa de Meia-Idade , Proteína SMARCB1/genéticaRESUMO
CONTEXT.: Molecular analysis of poorly differentiated/undifferentiated sinonasal neoplasms has resulted in identification of a growing number of genetically defined tumors. SMARCA4-deficient sinonasal carcinoma is one such recently described entity that emerged from within sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma (NEC), and teratocarcinosarcoma (TCS). OBJECTIVE.: To identify SMARCA4-deficient sinonasal carcinomas from a large institutional cohort of poorly differentiated/undifferentiated carcinomas and evaluate their clinicopathologic features. DESIGN.: SMARCA4/BRG1 immunohistochemistry was performed on all tumors diagnosed as SNUC, poorly differentiated carcinoma, NEC, and TCS during a 12-year period. SMARCA2/BRM and INSM1 immunostaining was performed in SMARCA4-deficient cases. RESULTS.: Twelve SMARCA4-deficient sinonasal carcinomas were identified among 299 cases. Morphologically, 5 cases were large cell NEC, 2 cases were small cell NEC, and 5 were TCS. SMARCA4 loss was diffuse and complete in 10 cases, while 2 cases showed focal retention. Most cases showed diffuse cytokeratin staining accompanied by weak, usually focal staining for chromogranin and synaptophysin. INSM-1 showed negativity in most cases. All cases showed retained SMARCA2 expression. IDH1/2 mutation was absent in all cases analyzed. Four of 7 patients died of disease, and aggressive multimodality treatment provided better outcome. CONCLUSIONS.: SMARCA4-deficient sinonasal carcinomas are morphologically akin to sinonasal poorly differentiated NECs and TCS, display cytokeratin positivity and only focal staining for neuroendocrine markers, and have aggressive biological behavior. Inclusion of SMARCA4 in the immunohistochemical panel for diagnostic workup of all sinonasal NEC and TCS phenotypes will facilitate their early recognition. Comprehensive germline and somatic mutational analyses of these tumors are necessary for further insights into their molecular pathogenesis.
Assuntos
Carcinoma Neuroendócrino , Neoplasias do Seio Maxilar , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , DNA Helicases/genética , Humanos , Imuno-Histoquímica , Queratinas , Neoplasias do Seio Maxilar/diagnóstico , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Proteínas Nucleares/genética , Proteínas Repressoras , Fatores de Transcrição/genéticaRESUMO
Sarcomatoid carcinoma of maxillary sinus tumor is extremely rare in head and neck tumors and has poor prognosis and frequently occurs to relapse locally after surgery. We first reported a case of locally advanced undifferentiated sarcomatoid carcinoma of right maxillary sinus with PDCD6-TERT fusion gene. The patient with a previous history of moderate alcohol drinking and smoking. The patient underwent surgical treatment. The tumor tissue using NGS analysis, no other driver gene mutations, and the PD-L1 IHC was negative. He received TPF regimen induction chemotherapy combined with anti-PD1 inhibitor and radiotherapy. The effect of treatment was good.
Assuntos
Carcinoma , Neoplasias de Cabeça e Pescoço , Neoplasias do Seio Maxilar , Telomerase , Proteínas Reguladoras de Apoptose , Proteínas de Ligação ao Cálcio , Humanos , Masculino , Seio Maxilar , Neoplasias do Seio Maxilar/diagnóstico por imagem , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/cirurgia , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown. METHODS: We evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788-6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion. RESULTS: Overall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/- CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling. CONCLUSION: Collectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.
Assuntos
Hidrolases de Éster Carboxílico/genética , Carcinoma/genética , Neoplasias do Seio Maxilar/genética , Recidiva Local de Neoplasia/epidemiologia , Proteínas de Fusão Oncogênica/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Superfície Celular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/terapia , Linhagem Celular Tumoral , Quimiorradioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Seguimentos , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias do Seio Maxilar/mortalidade , Neoplasias do Seio Maxilar/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estudos Retrospectivos , Adulto JovemRESUMO
Comprehensive molecular testing of individual tumors has led to the identification of novel molecularly defined cancer therapies and treatment indications. Given low frequencies of many molecular alterations, efficacy of therapies used to target them are often undefined, especially in the context of rare malignancies. Here we describe the first reported case of MET amplification in sinonasal undifferentiated carcinoma (SNUC), a rare cancer with a poor prognosis. The patient was treated with crizotinib, a tyrosine kinase inhibitor that targets c-MET, and experienced a complete response. Our report demonstrates the potential of employing precision oncology approaches in SNUC and other rare cancers.
Assuntos
Carcinoma/terapia , Crizotinibe/farmacologia , Neoplasias do Seio Maxilar/terapia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Carcinoma/diagnóstico por imagem , Carcinoma/genética , Carcinoma/patologia , Feminino , Amplificação de Genes/efeitos dos fármacos , Humanos , Neoplasias do Seio Maxilar/diagnóstico por imagem , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Terapia de Alvo Molecular , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
The skull base is the location of a wide variety of malignant tumors. Among them is sinonasal undifferentiated carcinoma (SNUC), a highly aggressive sinonasal neoplasm that was recently reclassified into subgroups of high-grade carcinomas with unique genomic events (e.g., SMARC-deficient carcinoma, nuclear protein in testis NUT carcinoma). Other high-grade carcinomas in this location are neuroendocrine carcinomas, sinonasal adenocarcinomas, and teratocarcinosarcomas. Given the rarity of these tumors, little transcriptomic data is available. The aim of this study was to characterize the immune-oncology gene expression profile in SNUC and other high-grade sinonasal carcinomas. Next-generation sequencing was performed in 30 high-grade sinonasal carcinoma samples using the HTG EdgeSeq Precision Immuno-Oncology Panel. Ingenuity pathway analysis was performed to understand the immunobiology, signaling, and functional perturbations during tumor development. The samples were divided into 3 groups: 21 SNUCs and SMARC-deficient sinonasal carcinomas; 5 high-grade neuroendocrine carcinomas (HGNECs), with small cell and large cell variants; and 4 high-grade sinonasal carcinomas (HGSNCs) of mixed histology (1 NUT carcinoma, 1 teratocarcinosarcoma, and 2 sinonasal adenocarcinomas). PRAME and ASCL1 emerged as upregulated transcripts with strong protein validation for SNUC and HGNEC; other upregulated candidates EZH2 and BRCA1 offer consideration for alternative targeted therapy, and downregulation of major histocompatibility complex molecules and chemokines represent another hurdle in the development of effective immunotherapy. This immune-oncology gene expression analysis of 3 groups of high-grade sinonasal carcinoma with emphasis on SNUC identified a number of differentially expressed transcripts reflecting effects on tumorigenesis. Identification of immune pathways should be further investigated for possible integration of immunotherapy into a multidisciplinary approach to these cancers and personalized treatment.
Assuntos
Carcinoma/genética , Carcinoma/imunologia , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma/patologia , Feminino , Humanos , Masculino , Neoplasias do Seio Maxilar/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , TranscriptomaRESUMO
INTRODUCTION: To describe the current state of literature involving SMARCB1/INI-1 deficient sinonasal carcinoma (SDSC) and examine a case at our institution. METHODS: A systematic search was performed using the Population, Intervention, Comparator, Outcome, and Study Design approach. Search criteria included all occurrences in the title or abstract of the terms: "integrase interactor 1 deficient," "INI1 deficient," or "SMARCB1 deficient" and "sinonasal carcinoma." The main outcomes were disease-free survival, all-cause mortality, rates of recurrence, or metastases. RESULTS: Systematic search yielded 13 studies for final review. All studies were either case series or case reports with 82 cases of SDSC published since 2014. Age on presentation ranged from 19 to 75 years, with the majority of patients being male. Surgical resection was the primary modality of treatment with adjuvant radiation or chemoradiation therapy. Overall, the prognosis was poor, with most tumors presenting at advanced stages with an overall median (range) survival of 22 (12-44) months with an average (standard deviation) of 45.3% (33.1%) of patients dying of the disease. An average (standard deviation) of 38.2% (34.0%) of patients had no evidence of disease at follow-up. Studies comparing sinonasal undifferentiated carcinoma to SDSC reported worse prognosis for SDSC and increased risk for locoregional recurrence in the latter cohort. CONCLUSIONS: SDSC represents a highly aggressive tumor presenting at advanced stage with propensity of metastasis. More research is necessary to determine the optimal treatment modality and management.
Assuntos
Carcinoma/genética , Neoplasias do Seio Maxilar/genética , Neoplasias Nasais/genética , Proteína SMARCB1/genética , Adulto , Idoso , Carcinoma/cirurgia , Feminino , Cefaleia/etiologia , Humanos , Masculino , Neoplasias do Seio Maxilar/cirurgia , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Neoplasias Nasais/cirurgia , Proteína SMARCB1/deficiência , Adulto JovemRESUMO
Since the first description of sinonasal undifferentiated carcinoma (SNUC) as a distinctive highly aggressive sinonasal neoplasm with probable origin from the sinonasal mucosa (Schneiderian epithelium), SNUC has been the subject of ongoing study and controversy. In particular, the SNUC category gradually became a "wastebasket" for any undifferentiated or unclassifiable sinonasal malignancy of definite or probable epithelial origin. However, with the availability of more specific and sensitive immunohistochemical antibodies and increasing implementation of novel genetic tools, the historical SNUC category became the subject of progressive subdivision leading to recognition of specific genetically defined, reproducible subtypes. These recently recognized entities are characterized by distinctive genetic aberrations including NUTM1-rearranged carcinoma (NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex such as SMARCB1-deficient and less frequently SMARCA4-deficient carcinoma. The ring became almost closed, with recent studies highlighting frequent oncogenic IDH2 mutations in the vast majority of histologically defined SNUCs, with a frequency of 82%. A review of these cases suggests the possibility that "true SNUC" probably represents a distinctive neoplastic disease entity, morphologically, phenotypically, and genetically. This review addresses this topic from a historical perspective, with a focus on recently recognized genetically defined subsets within the SNUC spectrum.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma/diagnóstico , Carcinoma/epidemiologia , Carcinoma/genética , DNA Helicases/genética , Humanos , Neoplasias do Seio Maxilar/diagnóstico , Neoplasias do Seio Maxilar/epidemiologia , Neoplasias do Seio Maxilar/genética , Proteínas Nucleares/genética , Proteína SMARCB1/genética , Fatores de Transcrição/genéticaRESUMO
A large number of tumor types arise from the mucosa of the sinonasal cavities. Although presenting clinically distinct behavior, due to poorly differentiated histologic features, they can be difficult to classify correctly. Our aim was to investigate whether IDH2 and IDH1 mutations may be specific to a subset of undifferentiated and poorly differentiated sinonasal carcinomas. A total of 125 tumor samples of 7 different histologic subtypes were analyzed for IDH mutations by sequencing and mutant-specific immunohistochemistry, and the results were correlated to clinical and follow-up data. The highest incidence of IDH2 mutations occurred in sinonasal undifferentiated carcinoma, with 11/36 (31%) cases affected. However, also, 1/9 neuroendocrine carcinomas, 2/4 high-grade non-intestinal-type adenocarcinomas, and 1/8 poorly differentiated squamous cell carcinomas carried the IDH2 mutation, whereas 1/48 intestinal-type adenocarcinomas harbored an IDH1 mutation. Immunohistochemical analysis of mutant IDH1/2 produced a number of false-negative results, but also 1 false-positive tumor was found. Disease-specific survival was more favorable in IDH2-mutant versus wild-type cases. Our data suggest that IDH-mutant sinonasal cancers, independent of their histologic subtype, may represent a distinct tumor entity with less aggressive clinical behavior. Clinically, patients with these mutations may benefit from specific IDH-guided therapies.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma/diagnóstico , Isocitrato Desidrogenase/genética , Neoplasias do Seio Maxilar/diagnóstico , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Carcinoma/patologia , Carcinoma/terapia , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Masculino , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Neoplasias do Seio Maxilar/terapia , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
Sinonasal carcinomas are head and neck tumours arising from the nasal cavity and paranasal sinuses characterized by unfavourable outcome, difficult treatment, diagnosis and prognosis. MicroRNAs are key molecules in the regulation of development and progression of cancer and their expression profiles could be used as prognostic biomarkers, to predict the patients' survival and response to treatment. In this study, we used quantitative realtime PCR with TaqMan® Advanced miRNA Assays to investigate the relative expression values of selected micro- RNAs in a unique set of formalin-fixed paraffin-embedded tissue samples obtained from 46 patients with sinonasal squamous cell carcinoma. Our results showed statistically significant up-regulation of three mature microRNAs: miR-9-5p (fold change: 6.80), miR-9-3p (fold change: 3.07) and let-7d (fold change: 3.93) in sinonasal carcinoma patients. Kaplan-Meier survival analysis and logrank test identified association between higher expression of miR-9-5p and longer survival of the patients (P = 0.0264). Lower expression of let-7d was detected in the patients with impaired survival, and higher expression of miR-137 was linked to shorter survival of the patients. We also identified several correlations between expression of the studied microRNAs and recorded clinicopathological data. Higher expression of miR-137 and lower expression of let-7d correlated with local recurrence (P = 0.045 and P = 0.025); lower expression of miR-9-5p and higher expression of miR-155-5p correlated with regional recurrence (P = 0.045 and P = 0.036). Higher expression of miR-9-3p correlated with occupational risk (P = 0.031), presence of vascular invasion (P = 0.013) and perineural invasion (P = 0.031). Higher expression of miR-155-5p was present in the samples originating from maxillary sinus (P = 0.011), cN1-3 classified tumours (P = 0.009) and G2-3 classified tumours (P = 0.017). In conclusion, our study supports the hypothesis of future prospect to use expression of miRNAs as prognostic biomarkers of squamous cell sinonasal carcinoma. In particular, miR-9-5p and miR-9-3p seem to be important members of the sinonasal cancer pathogenesis.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias do Seio Maxilar/genética , MicroRNAs/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias do Seio Maxilar/patologia , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Análise de RegressãoRESUMO
BACKGROUND: NUT midline carcinoma is a rare and aggressive subset of squamous cell carcinoma, which is characterized by the translocation of nuclear protein in testis gene that is mostly fused with bromodomain and extraterminal family proteins. We describe here the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion detected in a next-generation sequencing panel and we present the clinical evolution of this patient. CASE PRESENTATION: A 42-year-old Caucasian man was diagnosed with poorly differentiated squamous cell carcinoma of the left maxillary sinus, with negative in situ hybridization for Epstein-Barr encoding region and human papillomavirus genotyping. He received induction therapy, chemoradiotherapy with weekly systemic chemotherapy, and, concurrently, weekly intra-arterial chemotherapy. New imaging evaluation, 1 month after the end of the last treatment, revealed a good partial response in the primary lesion. However, positron emission tomography-computed tomography showed multiple suspicious lesions in his bones and lungs, which were histologically confirmed. He died exactly 2 months after metastatic disease was diagnosed. CONCLUSIONS: NUT midline carcinoma is usually very aggressive. Currently, there is no standard of care for treatment of NUT midline carcinoma. The definitive diagnosis must be by demonstration of NUTM1 rearrangement. Immunohistochemical staining of greater than 50% of tumor nuclei on formalin-fixed paraffin-embedded tissue using the monoclonal rabbit antibody to NUT (clone C52B1), has a specificity of 100%, and sensitivity of 87% for the diagnosis of NUT midline carcinoma. Our case is the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion.
Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Brasil , Evolução Fatal , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Neoplasias do Seio Maxilar/diagnóstico por imagem , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
OBJECTIVES: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer. Despite aggressive multimodal therapy, its prognosis remains poor. Because of its locally advanced nature and high propensity for distant metastasis, we frequently use induction chemotherapy before definitive therapy in patients with SNUC. However, about 30% of patients do not respond to induction chemotherapy, and lack of response is associated with a poor survival rate. Therefore, in this study, we performed gene expression analysis of SNUC samples to identify prognostic markers for induction chemotherapy response. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded SNUC tumor samples from previously untreated patients harvested before induction chemotherapy were used. Gene expression was performed using an oncology gene expression panel. RESULTS: We identified 34 differentially expressed genes that distinguish the responders from the non-responders. Pathway analysis using these genes revealed alteration of multiple pathways between the two groups. Of these 34 genes, 24 distinguished between these two groups. Additionally, 16 gene pairs were associated with response to induction therapy. CONCLUSION: We identified genes predictive of SNUC response to induction chemotherapy and pathways potentially associated with treatment outcome. This is the first report of identification of predictive biomarkers for response of SNUC to induction chemotherapy, and it may help us develop therapeutic strategies to improve the treatment outcomes of non-responders.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma/tratamento farmacológico , Carcinoma/genética , Neoplasias do Seio Maxilar/tratamento farmacológico , Neoplasias do Seio Maxilar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/patologia , Terapia Combinada/métodos , Feminino , Humanos , Quimioterapia de Indução/métodos , Masculino , Neoplasias do Seio Maxilar/patologia , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto JovemRESUMO
Sinonasal undifferentiated carcinoma (SNUC) is an aggressive malignancy harboring IDH2 R172 mutations in >80% cases. We explored the potential of genome-wide DNA methylation profiling to elucidate tumor biology and improve the diagnosis of sinonasal undifferentiated carcinoma and its histologic mimics. Forty-two cases, including sinonasal undifferentiated, large cell neuroendocrine, small cell neuroendocrine, and SMARCB1-deficient carcinomas and olfactory neuroblastoma, were profiled by Illumina Infinium Methylation EPIC array interrogating >850,000 CpG sites. The data were analyzed using a custom bioinformatics pipeline. IDH2 mutation status was determined by the targeted exome sequencing (MSK-IMPACTTM) in most cases. H3K27 methylation level was assessed by the immunohistochemistry-based H-score. DNA methylation-based semi-supervised hierarchical clustering analysis segregated IDH2 mutants, mostly sinonasal undifferentiated (n = 10) and large cell neuroendocrine carcinomas (n = 4), from other sinonasal tumors, and formed a single cluster irrespective of the histologic type. t-distributed stochastic neighbor embedding dimensionality reduction analysis showed no overlap between IDH2 mutants, SMARCB1-deficient carcinoma and olfactory neuroblastoma. IDH2 mutants demonstrated a global methylation phenotype and an increase in repressive trimethylation of H3K27 in comparison to IDH2 wild-type tumors (p < 0.001). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed no difference in pathway activation between IDH2-mutated sinonasal undifferentiated and large cell neuroendocrine carcinomas. In comparison to SMARCB1-deficient, IDH2-mutated carcinomas were associated with better disease-free survival (p = 0.034) and lower propensity for lung metastasis (p = 0.002). ARID1A mutations were common in small cell neuroendocrine carcinoma but not among IDH2 mutants (3/3 versus 0/18 and p < 0.001). IDH2 mutations in sinonasal carcinomas induce a hypermethylator phenotype and define a molecular subgroup of tumors arising in this location. IDH2-mutated sinonasal undifferentiated carcinoma and large cell neuroendocrine carcinoma likely represent a phenotypic spectrum of the same entity, which is distinct from small cell neuroendocrine and SMARCB1-deficient sinonasal carcinomas. DNA methylation-based analysis of the sinonasal tumors has potential to improve the diagnostic accuracy and classification of tumors arising in this location.
Assuntos
Carcinoma/diagnóstico , Metilação de DNA , Isocitrato Desidrogenase/genética , Neoplasias do Seio Maxilar/diagnóstico , Proteína SMARCB1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Carcinoma/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Pessoa de Meia-Idade , Mutação , Adulto JovemRESUMO
BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer. It is often difficult to determine whether SNUC is a distinct pathologic entity with poorly differentiated neuroendocrine features or it represents an undifferentiated tumor of squamous lineage. Also, reliable histopathologic markers that distinguish SNUC from poorly differentiated sinonasal squamous cell carcinoma (SNSCC) are lacking. Therefore, identification of new diagnostic molecular markers for SNUC is needed. METHODS: Treatment-naïve tumor specimens obtained from 15 SNUC and 6 SNSCC patients were used. Gene expression analysis was performed using an oncology panel. RESULTS: An unsupervised cluster analysis divided the patients into the one with only SNUCs and the one with mainly SNSCCs. Of 132 differentially expressed genes, 7 genes completely distinguished SNUCs from SNSCCs. SNUCs were enriched in sets of genes related to DNA repair, synthesis/replication, and cell division. CONCLUSIONS: Our study identified new diagnostic markers and potential therapeutic targets for SNUC.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma/diagnóstico , Expressão Gênica , Neoplasias do Seio Maxilar/diagnóstico , Neoplasias dos Seios Paranasais/diagnóstico , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma de Células Escamosas/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Neoplasias do Seio Maxilar/genética , Neoplasias dos Seios Paranasais/genética , RNA Neoplásico/metabolismo , Estudos RetrospectivosRESUMO
Epithelial sinonasal cancers (SNCs) are rare diseases with overlapping morphological features and a dismal prognosis. We aimed to investigate the expression differences among the histological subtypes for discerning their molecular characteristics. We selected 47 SNCs: (i) 21 nonkeratinizing squamous cell carcinomas (NKSCCs), (ii) 13 sinonasal neuroendocrine cancers (SNECs), and (iii) 13 sinonasal undifferentiated cancers (SNUCs). Gene expression profiling was performed by DASL (cDNA-mediated annealing, selection, extension, and ligation) microarray analysis with internal validation by quantitative RT-PCR (RT-qPCR). Relevant molecular patterns were uncovered by sparse partial-least squares discriminant analysis (sPLS-DA), microenvironment cell type (xCell), CIBERSORT, and gene set enrichment (GSEA) analyses. The first two sPLS-DA components stratified samples by histological subtypes. xCell highlighted increased expression of immune components (CD8+ effector memory cells, in SNUC) and "other cells": keratinocytes and neurons in NKSCC and SNEC, respectively. Pathway enrichment was observed in NKSCC (six gene sets, proliferation related), SNEC (one gene set, pancreatic ß-cells), and SNUC (twenty gene sets, some of them immune-system related). Major neuroendocrine involvement was observed in all the SNEC samples. Our high-throughput analysis revealed a good diagnostic ability to differentiate NKSCC, SNEC, and SNUC, but indicated that the neuroendocrine pathway, typical and pathognomonic of SNEC is also present at lower expression levels in the other two histological subtypes. The different and specific profiles may be exploited for elucidating their biology and could help to identify prognostic and therapeutic opportunities.