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BACKGROUND: The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need. METHODS: Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-H&N35]), progression-free survival and overall survival, duration of response, and toxicities. RESULTS: Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively. CONCLUSIONS: Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.
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Antineoplásicos/uso terapêutico , Carcinoma Adenoide Cístico/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Qualidade de Vida , Quinolinas/uso terapêutico , Neoplasias das Glândulas Salivares/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoide Cístico/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Compostos de Fenilureia/efeitos adversos , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/fisiopatologia , Análise de SobrevidaRESUMO
BACKGROUND: Pediatric salivary gland carcinomas (SGCs) are very rare. They differ from the adult SGCs in terms of epidemiologic and clinical behavior, being generally limited only to selected histotypes (e.g. low-grade mucoepidermoid [LG-MEC] and acinic cell cancer [AcCC]) and characterized by very good outcome. Our aim was to investigate therapeutic targets on a series of pediatric SGCs by immunohistochemical and molecular analysis. METHODS: A retrospective analysis was performed to search for cases of pediatric SGCs in the database of the Pediatric Oncology Unit at the Istituto Nazionale Tumori and in the Pathology database at the Gerhard-Seifert-Reference-Centre. The expressions of the most common tyrosine-kinase receptors (TKRs) reported in adult SGCs as EGFR, HER2, KIT and hormonal receptors (HRs) (estrogen α and ß, progesterone as well as androgen receptors) were investigated. CRTC1/MAML2 and MYB/NFIB were also analyzed in MEC and adenoid cystic carcinoma cases, respectively. RESULTS: Twenty-nine cases were identified: 22 MECs, 4 AcCCs, 1 adenoid cystic carcinoma (ACC), 1 adenocarcinoma not otherwise specified and 1 sialoblastoma. EGFR was the most expressed TKR, whilst HRs were negative in all cases except for ER-ß in four cases of MEC. CRTC1/MAML2 was present in 15 out of 17 evaluable MEC cases and MYB/NFIB was identified in the ACC case. CONCLUSIONS: The immunohistochemical and molecular profiles of pediatric SGCs analyzed in our series are similar to that observed in adults, especially for MEC, supporting a common biological background.
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Biomarcadores Tumorais/análise , Carcinoma/genética , Carcinoma/metabolismo , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/metabolismo , Adolescente , Criança , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Adamantinoma-like Ewing sarcoma (ALES) of the salivary glands is an exceedingly rare malignancy defined by the t(11,22) EWSR1::FLI1 fusion, with complex epithelial differentiation. To identify features that can allow for better recognition of this disease entity, we reviewed all published reports of molecularly confirmed ALES of the salivary glands and explored epidemiological, clinical, radiological, pathological, and therapeutic characteristics of a population of 21 patients including a single newly reported patient from our group. We searched the English-language literature indexed in PubMed, Medline, Scopus, and Web of Science using the keyword 'Adamantinoma-like Ewing sarcoma' published up to June 2022. The median age at diagnosis was 46 years, and a slight female sex predilection was observed. Most tumors originated in the parotid gland (86%) and presented as a painless palpable mass with a median diameter of 3.6 cm. Metastatic dissemination was reported only in one patient (5%), and after a median follow-up of 13 months the 1-year overall survival rate was 92%. Salivary gland ALES were frequently misdiagnosed at presentation (62% of cases) and were pathologically characterized by the presence of highly monomorphic small round blue cells with infiltrative pattern and positive immunostaining for CD99 and high- and low-molecular weight cytokeratins. Epidemiological and clinical features of salivary gland ALES raise questions on the incorporation of this malignancy in the Ewing sarcoma family tumor group.
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PURPOSE: Unresectable, locally advanced sinonasal epithelial tumours are rare diseases with poor prognosis. Multimodal approach is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT. METHODS: Patients with untreated, unresectable sinonasal epithelial tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enroled in a single-arm, open-label, phase II, multicentre clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype. Photon and/or proton/carbon-ion-based RT was employed according to disease site, stage and ICT response. Primary end-point was 5-years progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate per RECIST 1.1 and safety. RESULTS: Twenty-five patients were evaluable for primary end-point. Five-year PFS was 26.8% (95% confidence interval [CI]: 12.6-57.1), with a median PFS of 18 months. Five-year OS was 23.8% (95% CI: 9.5-59.3), with a median OS of 27 months. The overall response rate to ICT was 40%. Three-year PFS for patients achieving major volumetric partial response (mPRv) versus non-mPRv was 40% (95% CI: 13.7-100%) versus 23.1% (95% CI: 8.3-64.7%) (P = 0.318) and 3-year OS was 53.3% (95% CI: 21.4-100%) versus 37.7% (95% CI: 20.0-71.0%) (P = 0.114). CONCLUSION: Multimodal combination of ICT and innovative RT did not provide a significant improvement in survival rates with respect to previous experiences. This finding underscores the need for future research in this rare disease, still characterised by a heavy burden and poor prognosis. We observed longer survival in subjects achieving response to ICT. The overall treatment safety is acceptable.
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Carcinoma de Células Escamosas , Prótons , Humanos , Quimioterapia de Indução/métodos , Quimiorradioterapia/métodos , Cisplatino , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/terapia , CarbonoRESUMO
BACKGROUND: NUT carcinoma (NUTc) is a rare and aggressive malignant epithelial tumor characterized by rearrangement of the NUT gene on chromosome 15q14. METHODS: In this article, we present the fifth case worldwide of a young woman affected by a NUTc arising from a submandibular gland, presenting as a rapidly evolving mass. She underwent a right scialoadenectomy and received the initial diagnosis of high-grade mucoepidermoid carcinoma. Due to evidence of local recurrence at magnetic resonance imaging 1 month later, a subsequent right radical neck dissection was performed. The patient then sought a second opinion at our cancer center and finally received the correct diagnosis of NUT carcinoma. Given the well-known aggressive behavior of this neoplasm, as well as clinical and radiological features, she underwent adjuvant chemo-radiation (intensity-modulated radiotherapy + concurrent chemotherapy with cisplatin). RESULTS: After a disease-free interval of 2.6 months, a widespread metastatic disease led to rapid deterioration of performance status and patient death in a few weeks after metastatic onset. CONCLUSIONS: We presented a case of NUTc arising from salivary gland aiming to improve the knowledge of this rare malignancy. First, we pointed out that in the setting of rare tumors like salivary gland cancers, the diagnosis should be obtained by expert pathologists, and patients should be referred to tertiary cancer centers for their clinical management. Second, molecular profiling may help to identify possible druggable targets that may be exploited to treat patients suffering from this aggressive malignancy. Sharing the molecular data provided in this case will be useful for further research.
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Carcinoma , Neoplasias das Glândulas Salivares , Feminino , Humanos , Glândula Submandibular/patologia , Carcinoma/patologia , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/terapia , Radioterapia AdjuvanteRESUMO
Background: Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in almost 25-30% of androgen receptor (AR)-positive salivary gland carcinomas (SGCs), notably salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified (NOS). In the last years, several studies have reported the clinical benefit of HER2 directed therapies in this setting. This work aims at describing the natural history of AR-positive recurrent/metastatic (R/M) SGC patients, based on HER2 amplification status. Methods: Consecutive R/M AR-positive SGC patients accessing our Institution from 2010 to 2021 were analyzed. Descriptive statistics and survival analyses were performed to present the clinical characteristics of the selected patients and the outcomes, based on HER2 status. A specific focus was dedicated to patients developing metastases to the central nervous system (CNS). Results: Seventy-four R/M AR-positive SGC patients (72 men) were analyzed. Median follow-up was 36.18 months (95% CI 30.19-42.66). HER2 status was available in 62 cases (84%) and in 42% the protein was overexpressed (HER2+). Compared with patients with HER2- SGCs, in patients with HER2+ disease, HR for disease recurrence was 2.97 (95% CI 1.44-6.1, p=0.003), and HR for death from R/M disease was 3.22 (95% CI 1.39-7.49, p=0.007). Moreover, the HER2+ group showed a non-significant trend towards a higher prevalence of CNS metastases (40% vs. 24%, p=0.263). Patients developing CNS metastases had shorter survival than those who did not; at bivariate analysis (covariates: CNS disease and HER2 status), HER2 status demonstrated its independent prognostic significance. Discussion: In our patient population, HER2 amplification was a negative prognostic factor, and it was associated with a non-statistically significant higher risk of developing CNS metastasis. Further studies are needed to explore the potential clinical benefit of tackling the two biological pathways (AR and HER2) in patients affected by this rare and aggressive malignancy.
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OBJECTIVES: Plasma Epstein-Barr Virus (EBV)-DNA is a well-established prognostic biomarker in nasopharyngeal carcinoma (NPC). Different methods for assessment include single-copy gene targeted, European Conformity (CE)-marked assays, which are mostly employed in non-endemic settings, vs multiple-copy gene targeted, in-house BamHI-W based assays, which currently represent the most widely used method for EBV-DNA quantification. To date, evidence concerning the commutability of these different assays is still limited. MATERIALS AND METHODS: From August 2016 to March 2018, 124 plasma and 124 whole blood (WB) samples from 93 NPC patients were collected at different time-points for each patient. EBV-DNA viral load was quantified in pre- (n = 12) and post-treatment (n = 9), follow-up (n = 53), and recurrent/metastatic (R/M) (n = 50) phase. For each sample, one in-house BamHI-W vs three different CE-marked plasma assays were compared; the performance of plasma vs WB matrix was also assessed. Quantitative agreement of EBV-DNA values was evaluated by linear correlation and Bland-Altman analysis. RESULTS: A statistically significant (p = 0.0001) agreement between all CE-marked and the BamHI-W assays was found using plasma matrix, regardless of clinical phase. The results obtained in copies/ml were comparable to those expressed in IU/ml. When using WB matrix, the number of positive detections increased in the post-treatment phase. CONCLUSIONS: Our retrospective comparison supported an agreement between Plasma BamHI-W and CE-marked assays in measuring EBV-DNA for non-endemic NPC patients. There were no significant interferences from different measurement units (IU/ml vs copies/ml). Further evaluations are needed to better clarify the role of WB.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Estudos Retrospectivos , DNA ViralRESUMO
PURPOSE: The activity of androgen-deprivation therapy (ADT) in androgen receptor-positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC. METHODS: This was a single-institution phase II trial. A two-stage Simon's design was applied. The primary end point was confirmed objective response rate. Secondary end points were disease control rate, safety, progression-free survival, and overall survival. Patients were eligible when the following criteria were met: histologic diagnosis of AR-overexpressing SGC, measurable disease according to RECIST 1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and luteinizing hormone-releasing hormone agonist until progression or unacceptable toxicities. RESULTS: From 2015 to 2019, 24 AR+ patients with SGC (23 men; median age 65.8 years) were treated within the study. The overall response rate was 21% (5 partial responses), with a disease control rate of 62.5%. The median duration of response was 5.82 months. Median progression-free survival was 3.65 months (95% CI, 1.94 to 5.89), and median overall survival was 22.47 months (95% CI, 6.74 to not reached). Objective response to previous ADT did not correlate with the activity of abiraterone. Adverse events (AEs) were recorded in 22 cases (92%) with grade 3 AEs in six patients (25%): fatigue (two), flushing (one), supraventricular tachycardia (one), and two non-drug-related AEs. No drug-related grade 4 or 5 AEs were recorded. CONCLUSION: Abiraterone plus luteinizing hormone-releasing hormone agonist is active and safe as a second-line option in AR-expressing, castration-resistant SGC.
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Acetato de Abiraterona/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias das Glândulas Salivares/tratamento farmacológico , Acetato de Abiraterona/farmacologia , Adulto , Idoso , Antineoplásicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias das Glândulas Salivares/patologiaRESUMO
Under common therapeutic regimens, the prognosis of human papillomavirus (HPV)-positive squamous oropharyngeal carcinomas (OPCs) is more favorable than HPV-negative OPCs. However, the prognosis of some tumors is dismal, and validated prognostic factors are missing in clinical practice. The present work aimed to validate the prognostic significance of our published three-cluster model and to compare its prognostic value with those of the 8th edition of the tumor-node-metastasis staging system (TNM8) and published signatures and clustering models. METHODS: Patients with HPV DNA-positive OPCs with locoregionally advanced nonmetastatic disease treated with curative intent (BD2Decide observational study, NCT02832102) were considered as validation cohort. Patients were treated in seven European centers, with expertise in the multidisciplinary management of patients with head and neck cancer. The median follow-up was 46.2 months (95% CI, 41.2 to 50), and data collection was concluded in September 2019. The primary end point of this study was overall survival (OS). Three-clustering models and seven prognostic signatures were compared with our three-cluster model. RESULTS: The study population consisted of 235 patients. The three-cluster model confirmed its prognostic value. Two-year OS in each cluster was 100% in the low-risk cluster, 96.6% in the intermediate-risk cluster, and 86.3% in the high-risk cluster (P = .00074). For the high-risk cluster, we observed an area under the curve = 0.832 for 2-year OS, significantly outperforming TNM 8th edition (area under the curve = 0.596), and functional and biological differences were identified for each cluster. CONCLUSION: The rigorous clinical selection of the cases included in this study confirmed the robustness of our three-cluster model in HPV-positive OPCs. The prognostic value was found to be independent and superior compared with TNM8. The next step includes the translation of the three-cluster model in clinical practice. This could open the way to future exploration of already available therapies in HPV-positive OPCs tailoring de-escalation or intensification according to the three-cluster model.
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Alphapapillomavirus , Neoplasias de Cabeça e Pescoço , Expressão Gênica , Humanos , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genéticaRESUMO
Clinical data of ri-SGCs patients treated between 2015 and 2019 at a tertiary cancer center and a national hadron therapy facility were reviewed. Latent time (LT) from first RT to ri-SGCs diagnosis, overall (OS), and disease-free survival (DFS) were assessed. Thirteen patients developed 14 ri-SGCs (one patient had 2 synchronous ri-SCGs), after a median LT of 23 years (range 16-34). Parotid was the primary site in 8 cases (57%) and salivary duct carcinoma was the most frequent histotype (29%). Nine patients (69%) underwent surgery (Sx). Among them, 4 patients (31%) underwent Sx alone, 5 received post-operative treatments: 3 (23%) photon-based (X) reRT, one (8%) protons and carbon ions, one (8%) carbon ions only. One patient (8%) received definitive XRT. The remaining 3 patients (23%) received androgen deprivation therapy. With a median follow-up of 48 months (range 24-72), median OS and PFS were 74 and 24 months, respectively. In the subgroup of AR+ ri-SGCs, median PFS and OS were 12 and 74 months, respectively. Given the rarity of ri-SGCs, this work adds further knowledge to the paucity of literature. The management of these malignancies is extremely complex requiring a multidisciplinary treatment approach.
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Distant metastases (DM) in head and neck squamous cell carcinoma (HNSCC) remain a challenge as treatment options are limited. To identify biomarkers predictive of DM in primary tumors (PT), gene expression profiling was performed in PT from patients who did, or did not develop DM (T-with and T-without, n = 25 and 24, respectively), and in matched DM. A total of 185 and 42 differentially expressed genes were identified in the T-with vs. T-without and the T-with vs. DM comparisons, respectively. The intersection between these two comparisons identified COX7A1 and TBX5 as common genes. In three independent datasets, both genes were able to significantly distinguish patients according to their DM-free survival. By functional biological analyses, the T-without group showed enrichment in immune-response pathways, whereas the T-with group showed an enrichment in B-plasma cells and Tregs. Increased enrichment of proliferation-related pathways was observed in the T-with group compared with that in the DM group. Further comparisons with/without DM are needed to confirm these data in order to improve clinical management of HNSCC.
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OBJECTIVE: Outcomes of locally advanced epithelial sinonasal cancers remain unsatisfactory; moreover, only limited and heterogeneous data exist on prognostic factors. METHODS: We reviewed all consecutive patients with American Joint Committee Cancer stage III to IV epithelial sinonasal cancers treated with platinum-based induction chemotherapy (IC) followed by locoregional treatment between 1996 and 2015. RESULTS: We identified 69 patients treated with a multimodal approach (IC, surgery, radiotherapy). Overall, 44 patients recurred (64%). Of those, 19 patients received salvage surgery, but only four remained disease-free. Median overall survival (OS) was 62.5 months. Sinonasal neuroendocrine and small cell histotypes (P = 0.0085), neuroendocrine differentiation (P = 0.006), and lack of response to IC (P = 0.03) were associated with worse OS. In patients who recurred, median OS was 13 months since recurrence. Survival was longer in patients submitted to salvage surgery (44%) than in those receiving chemotherapy alone at recurrence (29.5 vs. 4.6 months). Patients with a clinical benefit after palliative chemotherapy had a longer median OS than those with disease progression (29.2 vs. 4.4 months; P < 0.0001). CONCLUSION: Globally, the prognosis of locally advanced epithelial sinonasal cancers is dismal, with worse outcomes for neuroendocrine lesions. In the recurrent setting, feasibility of salvage surgery and clinical benefit from palliative chemotherapy are associated with longer OS. A multimodal treatment strategy with IC seems to offer improved OS when compared with other retrospective series not employing such a therapeutic tool. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:857-865, 2020.
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Neoplasias dos Seios Paranasais/terapia , Adolescente , Adulto , Idoso , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Paliativos , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/patologia , Prognóstico , Terapia de SalvaçãoRESUMO
Schwannoma of the parotid gland is an uncommon tumor. When the facial nerve is involved by the tumor at the time of the operation, the surgical approach requires careful evaluation. The purpose of this study is to provide indications which can support the decision, taking into account the different clinical presentations of parotid schwannoma. In a retrospective study, eight cases of parotid schwannoma were collected between 1975 and 2006. In three cases the tumor affected the facial nerve itself and in the remaining ones it originated from intraparotid nonfacial peripheral nerves. When the facial nerve is involved by the tumor a conservative approach should always be considered. The indication for a surgical procedure should be discussed with the patient. If a conservative strategy is chosen, yearly follow-up by means of MRI and clinical observation should be planned.
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Neurilemoma/diagnóstico , Neurilemoma/cirurgia , Neoplasias Parotídeas/diagnóstico , Neoplasias Parotídeas/cirurgia , Adulto , Biópsia por Agulha Fina , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurilemoma/patologia , Neoplasias Parotídeas/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Skin adnexal cancers (SAC) are a heterogeneous group of rare malignancies with histological differentiation towards epithelial adnexa, which lack effective systemic treatments. The aim of this work is to identify any potentially druggable genomic alterations for possible targeted therapies. Cases of primary or recurrent/metastatic (RM) SAC between 2002 and 2014 were identified by searching the institutional cancer registration database. Histological sections of all referral cases were reviewed by a dedicated pathologist to confirm diagnosis. Immunohistochemistry was performed to assess the expression of androgen receptors (AR) and human epidermal growth factor receptor type 2 (HER2). Targeted next-generation sequencing (T-NGS) was performed to identify targetable mutations (panel of 50 genes analyzed by Cancer Hotspot Panel, Ion-Torrent Personal Genome Machine). Mutational analysis of the PTCH1 gene not present in the T-NGS panel was assessed by Sanger sequencing. A total of 45 cases with available histological samples were identified (35 primary, 10 RM). The most frequent histological type was porocarcinoma (n = 12). Globally, 14 cases (31%) were AR+ (6/10 RM, 60%; 8/35 primary, 23%). HER2 was shown as 2+ in eight of 42 (19%) cases (2/9 RM, 22%; 6/33 primary, 18%). DNA was adequate for T-NGS analysis in 25 cases. In the majority of cases (17 cases, 68%) at least one mutation in oncogenes or tumor suppressor genes was found: the most frequent ones involved TP.53 (13 cases, 76% of mutated SAC) and PIK3CA (three cases, 18%). The rate of PTCH1 mutation was 30%. These findings support the use of molecular screening in patients with advanced SAC.
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Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia/genética , Neoplasias de Anexos e de Apêndices Cutâneos/genética , Neoplasias das Glândulas Sebáceas/genética , Neoplasias das Glândulas Sudoríparas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Terapia de Alvo Molecular/métodos , Mutação , Taxa de Mutação , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Anexos e de Apêndices Cutâneos/tratamento farmacológico , Neoplasias de Anexos e de Apêndices Cutâneos/patologia , Receptor Patched-1/antagonistas & inibidores , Receptor Patched-1/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/tratamento farmacológico , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sudoríparas/tratamento farmacológico , Neoplasias das Glândulas Sudoríparas/patologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genéticaRESUMO
INTRODUCTION: Salivary gland cancers (SGCs) are a rare and heterogeneous group of malignant tumors arising from either major or minor salivary glands. Among SGCs patients, adenoid cystic carcinoma (ACC) is the most frequent histotype and its genetic aberrations are well known even though they are generally uncommon. Non-ACC subtypes are rarer and more heterogeneous than ACC from a histological and genomic point of view. In non-ACC, some altered molecular pathways [e.g. BRAF or RET mutations, Androgen Receptor (AR)] are potentially targetable with specific drugs. AREAS COVERED: A literature search was performed to summarize the main druggable genomic aberrations involving non-ACC SGCs. An overview of the genomics of non-ACC salivary gland malignancies is discussed. We describe the pattern of potentially targetable genomic alterations in non-ACC salivary gland malignancies according to their frequency rather than to the single non-ACC histotype. EXPERT OPINION/COMMENTARY: The genetic profiling through in-depth molecular analyses [e.g. Next-generation sequencing (NGS)] is advised in all patients affected by recurrent and/or metastatic non-ACC SGCs to find any potentially druggable target. Some histotypes may carry driving mutations that must be investigated and defined. For the rare cancers, access to a referral center is recommended to optimize the management of these patients.
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Antineoplásicos/farmacologia , Genômica , Neoplasias das Glândulas Salivares/tratamento farmacológico , Humanos , Terapia de Alvo Molecular , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores Androgênicos/genética , Neoplasias das Glândulas Salivares/genéticaRESUMO
BACKGROUND: Patients with prognosis recurrent/metastatic (R/M) salivary gland carcinomas (SGCs) are poor. Activity of axitinib was demonstrated in adenoid cystic carcinoma (ACC). We tested axitinib in a larger cohort of R/M SGCs including non-ACC. METHODS: Axitinib was administered at 10 mg daily (dose escalation allowed) until progression or unacceptable toxicity. Null hypothesis would be rejected if more than 3 of 26 responses were observed. RESULTS: Twenty-six patients (50% were male; 6 ACC, 20 non-ACC) were treated. Response rate was 8% (2 partial responses), 13 stable disease (>6 months in 7 patients) and 11 disease progression. Median progression-free survival and overall survival were 5.5 and 26.2 months, respectively. All patients had at least one adverse event: stomatitis (69%), fatigue (58%) and hypertension (54%) were the most frequent. CONCLUSIONS: This trial did not meet its primary endpoint hence axitinib should not be considered for further investigations in SGCs. Safety profile was in line with the scientific literature.
Assuntos
Axitinibe/uso terapêutico , Carcinoma Adenoide Cístico/tratamento farmacológico , Carcinoma Adenoide Cístico/mortalidade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/mortalidade , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Axitinibe/efeitos adversos , Carcinoma Adenoide Cístico/patologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Medição de Risco , Neoplasias das Glândulas Salivares/patologia , Análise de Sobrevida , Falha de TratamentoRESUMO
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.
Assuntos
Carcinoma Neuroendócrino/genética , Carcinoma de Células Escamosas/genética , Carcinoma/genética , Neoplasias do Seio Maxilar/genética , Doenças Raras/genética , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma/classificação , Carcinoma Neuroendócrino/classificação , Carcinoma de Células Escamosas/classificação , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Neoplasias do Seio Maxilar/classificação , Pessoa de Meia-Idade , Prognóstico , Doenças Raras/classificação , Estudos Retrospectivos , Microambiente Tumoral/genética , Adulto JovemRESUMO
The aim of this study is to compare 2 in situ hybridization (ISH) detection methods for human papilloma virus (HPV) 16 E6/E7 mRNA, that is, the RNAscope 2.0 High Definition (HD) and the upgraded RNAscope 2.5 HD version. The RNAscope 2.5 HD has recently replaced the RNAscope 2.0 HD detection kit. Therefore, this investigation starts from the need to analytically validate the new mRNA ISH assay and, possibly, to refine the current algorithm for HPV detection in oropharyngeal squamous cell carcinoma with the final goal of applying it to daily laboratory practice. The study was based on HPV status and on generated data, interpreted by a scoring algorithm. The results highlighted that the compared RNAscope HPV tests had a good level of interchangeability and enabled to identify oropharyngeal squamous cell carcinoma that are truly driven by high-risk HPV infection. This was also supported by the comparison of the RNAscope HPV test with HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction in a fraction of cases where material for HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction was available. Furthermore, the algorithm that associates p16 immunohistochemistry with the identification of HPV mRNA by RNAscope was more effective than the one that associated p16 immunohistochemistry with the identification of HPV DNA by ISH.
Assuntos
Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/isolamento & purificação , Proteínas Oncogênicas Virais/metabolismo , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/diagnóstico , Proteínas Repressoras/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patologia , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , RNA ViralRESUMO
Cancer progression through the mandible bone is still questioned. Once the tumor has eroded the cortex, it can extend vertically and laterally. It usually spreads in the medullary spaces and finally affects the alveolar nerve. The presence of the teeth has been considered as a relative barrier to cancer infiltration until now. Herein, we report an uncommon case of dental root invasion by adenoid cystic carcinoma of the floor of the mouth.