ABSTRACT
Malignant pleural effusion (MPE) from patients with advanced non-small-cell lung cancer (NSCLC) has been proven valuable for molecular analysis; however, simultaneous detection of driver fusions in MPE is still challenging. In this study, we investigated the Idylla™ GeneFusion Panel, a stand-alone test in tissue samples, in the evaluation of ALK, ROS1, RET and MET ex14 skipping mutations in MPE and compared its performance with routine reference methods (Real-time-based and Next-generation Sequencing-NGS). The inclusion criteria for sample selection were as follows: advanced NSCLC harboring ALK, ROS1, RET fusions or MET exon-skipping alterations and the availability of MPE collected at diagnosis or disease progression. Molecular alterations have been investigated on tissue by fluorescence in situ hybridization (FISH) or Real-time PCR or NGS. For molecular profiling with the Idylla™ GeneFusion, 200 µL of MPE supernatants combined with 50 µL of RNA Later solution were loaded into the Idylla™ cartridge without cfRNA extraction. The Idylla™ GeneFusion Assay performed on MPEs was able to confirm molecular profile, previously diagnosed with conventional methods, in all cases. Our data confirm that MPE are suitable material for investigating fusion alterations. The Idylla™ GeneFusion, although indicated for investigation of tissue samples, offers the possibility of performing a molecular characterization of supernatants without undertaking the entire cfRNA extraction procedure providing a rapid and reliable strategy for the detection of actionable genetic alterations.
Subject(s)
Carcinoma, Non-Small-Cell Lung , High-Throughput Nucleotide Sequencing , Lung Neoplasms , Real-Time Polymerase Chain Reaction , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , High-Throughput Nucleotide Sequencing/methods , Pilot Projects , Male , Female , Aged , Middle Aged , Real-Time Polymerase Chain Reaction/methods , Pleural Effusion, Malignant/genetics , Pleural Effusion, Malignant/pathology , Pleural Effusion, Malignant/diagnosis , Oncogene Proteins, Fusion/genetics , Gene Fusion , Adult , Mutation , Anaplastic Lymphoma Kinase/genetics , Aged, 80 and over , Proto-Oncogene Proteins c-ret/genetics , Protein-Tyrosine Kinases , Proto-Oncogene ProteinsABSTRACT
The current study assessed the performance of the fully automated RT-PCR-based Idylla™ GeneFusion Assay, which simultaneously covers the advanced non-small cell lung carcinoma (aNSCLC) actionable ALK, ROS1, RET, and MET exon 14 rearrangements, in a routine clinical setting involving 12 European clinical centers. The Idylla™ GeneFusion Assay detects fusions using fusion-specific as well as expression imbalance detection, the latter enabling detection of uncommon fusions not covered by fusion-specific assays. In total, 326 archival aNSCLC formalin-fixed paraffin-embedded (FFPE) samples were included of which 44% were resected specimen, 46% tissue biopsies, and 9% cytological specimen. With a total of 179 biomarker-positive cases (i.e., 85 ALK, 33 ROS1, 20 RET fusions and 41 MET exon 14 skipping), this is one of the largest fusion-positive datasets ever tested. The results of the Idylla™ GeneFusion Assay were compared with earlier results of routine reference technologies including fluorescence in situ hybridization, immunohistochemistry, reverse-transcription polymerase chain reaction, and next-generation sequencing, establishing a high sensitivity/specificity of 96.1%/99.6% for ALK, 96.7%/99.0% for ROS1, 100%/99.3% for RET fusion, and 92.5%/99.6% for MET exon 14 skipping, and a low failure rate (0.9%). The Idylla™ GeneFusion Assay was found to be a reliable, sensitive, and specific tool for routine detection of ALK, ROS1, RET fusions and MET exon 14 skipping. Given its short turnaround time of about 3 h, it is a time-efficient upfront screening tool in FFPE samples, supporting rapid clinical decision making. Moreover, expression-imbalance-based detection of potentially novel fusions may be easily verified with other routine technologies without delaying treatment initiation.
Subject(s)
Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung , Exons , Lung Neoplasms , Oncogene Proteins, Fusion , Protein-Tyrosine Kinases , Proto-Oncogene Proteins c-met , Proto-Oncogene Proteins c-ret , Proto-Oncogene Proteins , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Proto-Oncogene Proteins c-ret/genetics , Anaplastic Lymphoma Kinase/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins c-met/genetics , Exons/genetics , Proto-Oncogene Proteins/genetics , Oncogene Proteins, Fusion/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Gene Rearrangement , In Situ Hybridization, Fluorescence/methods , Multiplex Polymerase Chain ReactionABSTRACT
BACKGROUND: Castleman disease (CD) comprises a group of rare and heterogeneous haematological disorders, including unicentric (UCD) and multicentric (MCD) forms, the latter further subdivided into HHV8-MCD, POEMS-MCD and idiopathic-MCD (iMCD). However, according to the Castleman Disease Collaborative Network guidelines, the diagnosis of CD can only be achieved through collaboration between clinicians and pathologists. METHODS: We applied these clinical and pathological criteria and implement with clonality testing to a retrospective cohort of 48 adult and paediatric Italian patients diagnosed with reactive lymphadenitis with CD-like histological features. RESULTS: We confirmed the diagnosis of CD in 60% (29/48) of the cases, including 12 (41%) UCD and 17 (59%; five HHV8-MCD, three POEMS-MCD and nine iMCD) MCD. Of the remaining 19 cases (40%) with multiple lymphadenopathy, 5 (26%) were classified as autoimmune diseases, 1 (5%) as autoimmune lymphoproliferative disorder, 1 (5%) as IgG4-related disease, 11 (83%) as reactive lymphadenitis and 1 (5%) as nodal marginal zone lymphoma. CONCLUSIONS: Our study emphasizes the importance of the multidisciplinary approach to reactive lymphadenitis with CD-like features in order to achieve a definitive diagnosis and choose the appropriate treatment.
Subject(s)
Castleman Disease , Lymphadenitis , Lymphadenopathy , Lymphoma, B-Cell, Marginal Zone , Adult , Humans , Child , Castleman Disease/diagnosis , Retrospective StudiesABSTRACT
Thyroid cytological examination, a key tool in preoperative thyroid nodule evaluation, is specific and accurate; some drawbacks are due to inadequate or indeterminate cytological reports and there is a need for an innovative approach overcoming the limits of traditional cytological diagnostics. Fluorescence laser confocal microscopes (FCM) is a new optical technique for allowing immediate digital imaging of fresh unfixed tissues and real-time assessment of sample adequacy and diagnostic evaluation for small biopsies and cytological samples. Currently, there are no data about the use of FCMs in the field of thyroid nodular pathology. The aims of this study were to test FCM technology for evaluating the adequacy of FNA samples at the time of the procedure and to assess the level of concordance between FCM cytological evaluations, paired conventional cytology, and final surgical histology. The secondary aim was to define the integrity of nucleic acids after FCM evaluation through NGS molecular analysis. Sample adequacy was correctly stated. Comparing FCM evaluation with the final histology, all cases resulting in malignant or suspicious for malignancy at FCM, were confirmed to be carcinomas (PPV 100%). In conclusion, we describe a successful application of FCM in thyroid preoperative cytological evaluation, with advantages in immediate adequacy assessment and diagnostic information, while preserving cellular specimens for permanent morphology and molecular analysis, thus improving timely and accurate patient management.
ABSTRACT
Lung cancer remains the leading cause of cancer deaths worldwide. International societies have promoted the molecular analysis of MET proto-oncogene, receptor tyrosine kinase (MET) exon 14 skipping for the clinical stratification of non-small cell lung cancer (NSCLC) patients. Different technical approaches are available to detect MET exon 14 skipping in routine practice. Here, the technical performance and reproducibility of testing strategies for MET exon 14 skipping carried out in various centers were evaluated. In this retrospective study, each institution received a set (n = 10) of a customized artificial formalin-fixed paraffin-embedded (FFPE) cell line (Custom METex14 skipping FFPE block) that harbored the MET exon 14 skipping mutation (Seracare Life Sciences, Milford, MA, USA), which was previously validated by the Predictive Molecular Pathology Laboratory at the University of Naples Federico II. Each participating institution managed the reference slides according to their internal routine workflow. MET exon 14 skipping was successfully detected by all participating institutions. Molecular analysis highlighted a median Cq cut off of 29.3 (ranging from 27.1 to 30.7) and 2514 (ranging from 160 to 7526) read counts for real-time polymerase chain reaction (RT-PCR) and NGS-based analyses, respectively. Artificial reference slides were a valid tool to harmonize technical workflows in the evaluation of MET exon 14 skipping molecular alterations in routine practice.
ABSTRACT
A range of different techniques are available for predictive biomarker testing for non-small-cell lung cancer (NSCLC) clinical management. International guidelines suggest next-generation sequencing (NGS) as the preferred procedure, but other reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods are rapidly evolving. In this study, we evaluated the reliability and accuracy of the IdyllaTM GeneFusion assay, a rapid and fully automated platform able to simultaneously detect ALK, ROS1, RET and NTRK1/2/3 and MET ex14 skipping mutations and compared its performance with routine reference methods. The cohort included thirty-seven NSCLCs plus two parotid gland carcinomas, previously characterized for the above alterations through either IHC, FISH, RT-PCR or NGS. In 36 of 39 cases, the Idylla GeneFusion assay and the reference methods were concordant (overall agreement: 92.3%). Tumor sections stored at room temperature for up to 60 days and 17 cases older than 2 years were successfully characterized. Our results suggest that the Idylla GeneFusion assay is a reliable tool to define gene fusion status and may be a valuable stand-alone diagnostic test when time efficiency is needed or NGS is not feasible.
ABSTRACT
OBJECTIVES: This study aimed to compare the costs of a next-generation sequencing-based (NGS-based) panel testing strategy to those of a single-gene testing-based (SGT-based) strategy, considering different scenarios of clinical practice evolution. METHODS: Three Italian hospitals were analysed, and four different testing pathways (paths 1, 2, 3, and 4) were identified: two for advanced non-small-cell lung cancer (aNSCLC) patients and two for unresectable metastatic colon-rectal cancer (mCRC) patients. For each path, we explored four scenarios considering the current clinical practice and its expected evolution. The 16 testing cases (4 scenarios × 4 paths) were then compared in terms of differential costs between the NGS-based and SGT-based approaches considering personnel, consumables, equipment, and overhead costs. Break-even and sensitivity analyses were performed. Data gathering, aimed at identifying the hospital setup, was performed through a semi-structured questionnaire administered to the professionals involved in testing activities. RESULTS: The NGS-based strategy was found to be a cost-saving alternative to the SGT-based strategy in 15 of the 16 testing cases. The break-even threshold, the minimum number of patients required to make the NGS-based approach less costly than the SGT-based approach, varied across the testing cases depending on molecular alterations tested, techniques adopted, and specific costs. The analysis found the NGS-based approach to be less costly than the SGT-based approach in nine of the 16 testing cases at any volume of tests performed; in six cases, the NGS-based approach was found to be less costly above a threshold (and in one case, it was found to be always more expensive). Savings obtained using an NGS-based approach ranged from 30 to 1249 per patient; in the unique testing case where NGS was more costly, the additional cost per patient was 25. CONCLUSIONS: An NGS-based approach may be less costly than an SGT-based approach; also, generated savings increase with the number of patients and different molecular alterations tested.
ABSTRACT
Carcinomas of the thyroid with Ewing family tumor elements (CEFTEs) are small cell thyroid tumors characterized by epithelial differentiation and EWSR1-FLI1 rearrangements. In contrast to primary thyroid Ewing sarcomas, these rare tumors have a favorable prognosis. CEFTEs may co-exist with papillary thyroid carcinoma (PTC) foci and are thought to arise from either PTCs or main cells of solid cell nests (SCN). Due to their rare occurrence, characteristic clinical presentations, preoperatory sonographic (US) findings, and fine-needle aspiration (FNA) cytologic features were ill-defined until now. We report a case of a 40-year-old male who was referred to the thyroid clinic for a progressively enlarging, hard, painless, cervical mass. US examination revealed a hypoechoic nodule with lobulated margins and scant intranodular vascular signals of the right thyroid lobe. Evidence of extracapsular spread was not identified. FNA provided a Bethesda V cytology classification on conventional smears. Repeat FNA sampling with the use of a CytoFoam Core allowed a preoperative diagnosis consistent with undifferentiated thyroid carcinoma. Total thyroidectomy without lymph node dissection was performed. Histologic examination with subsequent molecular studies provided the diagnosis of papillary carcinoma of the thyroid with Ewing family tumour elements (CEFTEs). No additional treatment was rendered and the patient showed no evidence of local or distant disease by clinical examination, US, and 18FDG-TAC/PET after 6 months of follow-up. This is the first reported case of CEFTE with complete clinical, US, cytologic, and immunohistochemical preoperatory assessment.
Subject(s)
Thyroid Cancer, Papillary/diagnosis , Thyroid Neoplasms/diagnosis , Adult , Humans , Male , Oncogene Proteins, Fusion/genetics , Thyroid Cancer, Papillary/genetics , Thyroid Cancer, Papillary/pathology , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathologyABSTRACT
The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients' evaluation. METHODS: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model. RESULTS: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001). CONCLUSIONS: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management.
ABSTRACT
Despite remarkable therapeutic advances have been made in the last few decades, non-small cell lung cancer (NSCLC) is still one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies and in particular NSCLC. Brain-derived neurotrophic factor (BDNF), binding its high-affinity tyrosine kinase B receptor, has been shown to promote cancer progression and metastasis. We hereby investigated the expression of the BDNF and its TrkB receptor in its full-length and truncated isoform T1, in samples from primary adenocarcinomas (ADKs) of the lung and in their metastasis to evaluate if their expression was related to preferential tumor entry into the central nervous system (CNS). By immunohistochemistry, 80% of the ADKs that metastasize to central nervous system expressed TrkB receptor compared to 33% expressing of ADKs without CNS metastasis. Moreover, ADKs with CNS metastasis showed an elevated expression of the full-length TrkB receptor. The TrkB receptor FL/T1 ratio was statistically higher in primary ADKs with brain metastasis compared to ADKs without brain metastasis. Our data indicate that TrkB full-length isoform expression in primary ADK cells may be associated with higher risk to develop brain metastasis. Therefore, TrkB receptor may possess prognostic and therapeutic implications in lung ADK.
Subject(s)
Brain Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Mutation/genetics , Receptor, trkB/genetics , Aged , Brain-Derived Neurotrophic Factor/metabolism , Cell Adhesion , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Receptor, trkB/metabolism , Spheroids, Cellular/metabolism , Spheroids, Cellular/pathologyABSTRACT
The increased frequency of thyroid nodules is paralleled by the rise of thyroid cancer diagnosis. To define the nature of most thyroid nodules, fine needle aspiration (FNA) followed by cytological evaluation is considered the method of choice. About 20% of FNA biopsies on thyroid nodules, however, show indeterminate cytological features and may require diagnostic surgery. Several immunocytochemical and molecular markers have been proposed to improve classification of thyroid nodules, but these tests require adequate cell amount and cytological paraffin inclusion. Polymeric matrices were recently proposed for the collection of cells for diagnostic purposes. In this study, we evaluated the diagnostic use of a new matrix (CytoMatrix). Morphological, molecular and immunohistochemical investigations were carried out on 23 FNA samples included in CytoMatrix and compared with data obtained from the definitive histology of surgical samples. Our results showed that CytoMatrix is suitable to capture and preserve the cellularity of the samples harvested by FNA and that its paraffin sections mimic the morphology of those obtained from real histological tissue. Immunohistochemistry on CytoMatrix samples was consistent with the immunophenotypical profile of the corresponding histological surgical specimens. Mutational analysis of the BRAF (V600E) gene performed on CytoMatrix inclusions and paired surgical tissue matched in all but one cases while matrix immunohistochemistry identified 91.6% of BRAF mutated samples. In conclusion, we suggest that CytoMatrix could be a reliable tool to overcome the current limits of traditional collection methods for the study of thyroid cytology, thereby improving their reliability for a conclusive diagnostic interpretation.
ABSTRACT
Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by repeated episodes of upper airways collapse during the sleep. The following intermittent hypoxia triggers a state of chronic inflammation, which also interests the nervous system leading to neuronal damage and increased risk of cognitive impairment. Brain derived neurotrophic factor (BDNF) is a growth factor often associated with neuroplasticity and neuroprotection whose levels increase in several condition associated with neuronal damage. However, whether patients affected by OSAS have altered BDNF levels and whether such alteration may be reflective of their cognitive impairment is still controversial. Here we show that, when compared to healthy control volunteers, OSAS patients have increased serum levels of BDNF. Moreover, OSAS patients with the higher levels of BDNF also have reduced neurocognitive impairment as measured by The Montreal Cognitive Assessment (MoCA) questionnaire. Treatment with standard non-invasive mechanical ventilation (CPAP) also was able to ameliorate the level of cognitive impairment. Altogether our results indicate that BDNF levels represent a neuroprotective response to intermittent hypoxia in OSAS patients.
Subject(s)
Brain-Derived Neurotrophic Factor/blood , Sleep Apnea, Obstructive/blood , Aged , Cognition , Cognitive Dysfunction/blood , Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/therapy , Female , Humans , Male , Middle Aged , Protective Factors , Respiration, Artificial , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/therapySubject(s)
B7-H1 Antigen , Chromosomes, Human, Pair 9 , Epstein-Barr Virus Infections , Gene Expression Regulation, Neoplastic , Herpesvirus 4, Human/metabolism , Hodgkin Disease , Neoplasm Proteins , B7-H1 Antigen/biosynthesis , B7-H1 Antigen/genetics , Child , Child, Preschool , Chromosomes, Human, Pair 9/genetics , Chromosomes, Human, Pair 9/metabolism , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/metabolism , Epstein-Barr Virus Infections/virology , Female , Hodgkin Disease/genetics , Hodgkin Disease/metabolism , Hodgkin Disease/virology , Humans , Infant , Male , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/geneticsABSTRACT
Epstein-Barr virus (EBV)-related lymphoproliferative disorders are relatively common in Iraqi children. Burkitt lymphoma (BL) accounted for 40% of lymphoma cases. The mean age of 125 BL cases was 5.9 ± 3.1 years, and the male-to-female ratio was 3.6:1. Clinical presentation was abdominal in 66% and head and neck in 34%. Bone marrow involvement was higher (P < 0.001) in children with head and neck disease. Tumor cells had MYC translocation (96%) and were CD20+ /CD10+ /MYC+ /BCL2- . MUM1/IRF4 staining was expressed by a fraction of tumor cells in 19 of 125 cases (15%) and was more frequent (P < 0.007) in head and neck disease (12/42; 29%). EBV-encoded RNA was positive in 100 of 125 (80%) BL cases.
Subject(s)
Burkitt Lymphoma/epidemiology , Burkitt Lymphoma/pathology , Burkitt Lymphoma/virology , Biomarkers, Tumor/analysis , Child , Child, Preschool , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/epidemiology , Female , Head and Neck Neoplasms/epidemiology , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/virology , Humans , Incidence , Interferon Regulatory Factors/biosynthesis , Iraq/epidemiology , MaleABSTRACT
Cytokine production is essential for follicular dendritic cell (FDC) maintenance and organization of germinal centres. In follicular lymphoma, FDCs are often disarrayed and may lack antigens indicative of terminal differentiation. We investigated the in situ distribution of cells producing lymphotoxin-beta (LTB), lymphotoxin-alpha (LTA), and tumour necrosis factor-alpha (TNFA) transcripts in human reactive lymph nodes and in follicular lymphomas with follicular or diffuse growth pattern. LTB was the cytokine most abundantly produced in germinal centres. LTB was present in nearly 90% of germinal centre cells whereas LTA and TNFA were detected in 30 and 50%, respectively. Moreover, the amount of LTB expressed in reactive germinal centre cells was 80-fold higher than that of LTA and 20-fold higher than that of TNFA. LTB-positive cells were more numerous in the germinal centre dark zone, whereas expression of the FDC proteins CD21, CD23, VCAM, and CXCL13 was more intense in the light zone. Tumour cells of follicular lymphomas produced less LTB than reactive germinal centre cells. The results of the in situ study were confirmed by RT-PCR; LTB was significantly more abundant in reactive lymph nodes than in follicular lymphoma, with the lowest values detected in predominantly diffuse follicular lymphoma. In neoplastic follicles, low production of LTB by tumour B cells was associated with weaker expression of CD21+/CD23+ by FDCs. Our findings detail for the first time the distribution of LTA-, LTB-, and TNFA-producing cells in human reactive germinal centres and in follicular lymphoma. They suggest the possibility that impaired tumour-cell LTB production may represent a determinant of FDC phenotype loss and for defective follicular organization in follicular lymphoma.
Subject(s)
Lymphoma, Follicular/metabolism , Lymphotoxin-beta/metabolism , Adult , Aged , Aged, 80 and over , Child , Dendritic Cells, Follicular/metabolism , Female , Germinal Center/metabolism , Humans , Immunohistochemistry , In Situ Hybridization , Lymph Nodes/metabolism , Lymphoma, Follicular/pathology , Lymphotoxin-alpha/genetics , Lymphotoxin-alpha/metabolism , Lymphotoxin-beta/genetics , Male , Middle Aged , PhenotypeABSTRACT
We used optimized immunohistochemistry (IHC) with the D5F3 antibody for detection of tumours in a prospective study of 307 pulmonary adenocarcinomas. Cases positive by IHC (1+, 2+, 3+) were further investigated by fluorescent in situ hybridization (FISH). Of 307 cases, 22 (7.2%) were moderately intensely positive (2+/3+); 18 of these (82%) were also positive by FISH. Of the four IHC-positive/FISH-negative cases, one was unsuitable for FISH and three had abnormalities of the ALK gene. All cases with weak reactivity with D5F3 (1+) were FISH-negative. The FISH positive/IHC-positive cases with moderately intense reactivity had the typical clinicopathologic features of ALK-positive patients (younger age, p < 0.01; higher frequency in metastatic sites, p < 0.01; cribriform/mucinous/signet histology, p < 0.01; stage IV disease, p < 0.01). In conclusion, our findings indicate that optimized IHC using the D5F3 antibody provides a reliable and inexpensive test for identification of ALK-positive adenocarcinomas. Inclusion of this information in the pathology report at the time of the histological diagnosis might significantly shorten time to treatment.
Subject(s)
Adenocarcinoma/diagnosis , Biomarkers, Tumor/analysis , Immunohistochemistry/methods , Lung Neoplasms/diagnosis , Receptor Protein-Tyrosine Kinases/biosynthesis , Adenocarcinoma of Lung , Adult , Aged , Anaplastic Lymphoma Kinase , Antibodies, Monoclonal , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Prospective Studies , Receptor Protein-Tyrosine Kinases/analysisABSTRACT
Sinonasal melanomas are rare neoplasms with poor prognosis that may harbor KIT and NRAS genes mutations. Molecular alterations represent possible targets of tailored therapeutic approaches. We describe the case of a 74-year-old patient with primary melanoma of the nasal cavity. Mutational analysis of KIT demonstrated a point missense mutation D820G in exon 17. This represents, to our knowledge, the first case of sinonasal melanoma harboring this specific KIT mutation. Although KIT mutations confer sensibility to thyrosine-kinase inhibitor, it has been proved that this is strongly dependent on the region in which this alteration occurs. Thus it seems very important to perform an accurate gene mutational analysis to provide a biological rationale to the tailored therapy.
Subject(s)
Exons , Melanoma/diagnosis , Mutation , Nose Neoplasms/diagnosis , Paranasal Sinuses/pathology , Proto-Oncogene Proteins c-kit/genetics , Aged , Humans , Male , Melanoma/genetics , Nose Neoplasms/geneticsABSTRACT
OBJECTIVES: To investigate prevalence and age-distribution of ALK- or ROS1-translocated adenocarcinomas in patients ≤50 years of age. MATERIALS AND METHODS: Paraffin sections of pulmonary adenocarcinoma were analyzed for ALK (637 cases) and ROS1 (376 cases) translocations using FISH, and for EGFR mutations (789 cases) using mutant-specific Real-Time PCR. RESULTS: ALK or ROS1 fusions were detected in 55 of 637 cases (8.6%). When patients were stratified for age, it was found that six of six cases (100%) of lung adenocarcinoma diagnosed in patients <30 years of age were translocated for ALK (4 cases) or ROS1 (2 cases). With the increase of age, there was a gradual decrease in the percentage of positive cases. In fact, ALK-translocated or ROS1-translocated cases were 5 of 17 cases (29%) in the 31-40 years age-group, 6 of 46 cases (13%) in the 41-50 years age-group, and 38 of 568 cases (7.0%) in patients older than 50 years. The six patients <30 years of age (5F/1M), including two pediatric patients (≤18 years old), presented with stage IV disease, were never or light smoker, and had no family history of pulmonary tumours. Four of the six patients, were treated with crizotinib and had an objective response. CONCLUSIONS: Our findings provide evidence that ALK or ROS1 translocations are crucial events in tumourigenesis of pulmonary adenocarcinoma of very young patients, including pediatric patients.