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The combination of neuroendocrine/non neuroendocrine lung tumors (CNNELT) mentioned in the last edition of the World Health Organization (WHO) of Thoracic Tumors refers to small cell carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC) mixed with any other non-small cell lung carcinoma (NSCLC). Typical Carcinoid (TC)/Atypical Carcinoid (AC) combined with NSCLC is not included among this category. However, case reports of TC/AC combined with NSCLC have been described. We previously reported 2 cases of lung adenocarcinoma (LUA) mixed with carcinoid sharing mutations in both components supporting the hypothesis of a clonal origin. We extended our analysis to other four cases of mixed NSCLC-carcinoid by performing targeted-DNA and RNA-based NGS analysis in both primary and their paired lymph nodes metastasis. In all cases, LUA and AC components shared at least 1 common mutation (KRAS driver mutation p.Gly12Val in cases 1 and 3, AKAP13-RET fusion in case 2, and missense KRAS driver mutation p.Gly12Ala in case 4, reinforcing the hypothesis of a clonal origin. Moreover, the same mutation was detected in the metastasis constituted only by AC (cases 2 and 4). Although it is a rare malignancy in the lung, mixed LUA and TC/AC could be included among the histotypes for which a deep molecular characterization of both components is needed to identify the presence of potential druggable genetic alterations.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Tumor Carcinoide , Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Pequenas , Neoplasias Pulmonares , Tumores Neuroendócrinos , Humanos , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , Carcinoma de Células Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Tumor Carcinoide/genética , Tumor Carcinoide/patologia , Tumores Neuroendócrinos/patologia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Adenocarcinoma de Pulmão/patologiaRESUMO
Anaplastic lymphoma kinase (ALK) fusions account for 5-7% of non-small cell lung cancer (NSCLC) patients, the therapeutic approaches for which have significantly evolved in the last few years. However, the response to target therapies remains heterogeneous, partially due to the many different ALK fusion variants reported to date. Rare fusion variants have also been discovered, but their role in influencing responses to ALK inhibitors (ALKis) remains poorly elucidated. Laboratory investigation at both the tissue and protein levels, and a molecular profile by next-generation sequencing (NGS) were performed on a lung biopsy sample from one patient with poorly differentiated adenocarcinoma. An in silico prediction model using ColabFold software v1.5.5 was used to model and predict the entire structure of the chimeric aberrant ALK protein. Here, we report a case of a former smoker, a 60-year-old man, diagnosed with NSCLC and undergoing ALK translocation. He received first-, second- and third-generation ALK protein inhibitors (ALKis), showing a clinical benefit for about 4 years. IHC analysis and the molecular examination of the tissue biopsy indicated a positive staining for ALK and a novel ALK gene fusion variant, involving the sperm antigen with calponin homology and coiled-coil domain 1-like (SPECC1L) gene with an unreported breakpoint in exon 7. The novel SPECCL1::ALK fusion was identified using Anchored Multiplex PCR (AMP)-NGS technology and was predicted to retain the Pkinase_Tyr domain at the carboxy-terminal region of the resulting chimeric protein. To the best of our knowledge, this is the first case of an ALK-positive NSCLC patient carrying the SPECC1L exon 7 fusion breakpoint and one of the few reports about clinical outcomes related to SPECC1L::ALK fusion. The in silico hypothesized biological role of this newly identified fusion variant corroborates the observed clinical response to multiple ALKis. The molecular findings also reinforce the utility of AMP-based NGS technology as a valuable tool for the identification of rare chromosomal events that may be related to the variability of patient outcomes to different ALKis treatments.
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Background. Limited studies and observations conducted on a too small number of patients prevent determining the actual clinical utility of pulmonary contrast-enhanced ultrasound (CEUS). The aim of the present study was to examine the efficacy of contrast enhancement (CE) arrival time (AT) and other dynamic CEUS findings for differentiating between malignant and benign peripheral lung lesions. Methods. 317 inpatients and outpatients (215 men, 102 women; mean age: 52 years) with peripheral pulmonary lesions were included in the study and underwent pulmonary CEUS. Patients were examined in a sitting position after receiving an intravenous injection of 4.8 mL of sulfur hexafluoride microbubbles stabilized by a phospholipid shell as ultrasound contrast agent (SonoVue-Bracco; Milan, Italy). Each lesion was observed for at least 5 min in real-time and the following temporal characteristics of enhancement were detected: the arrival time (AT) of microbubbles in the target lesion; the enhancement pattern; the wash-out time (WOT) of microbubbles. Results were then compared in light of the definitive diagnosis of community acquired pneumonia (CAP) or malignancies, which was not known at the time of CEUS examination. All malignant cases were diagnosed by histological results, while pneumonia was diagnosed on the basis of clinical and radiological follow-up, laboratory findings and, in some cases, histology. Results. CE AT has not been shown to differ between benign and malignant peripheral pulmonary lesions. The overall diagnostic accuracy and sensibility of a CE AT cut-off value < 10 s in discriminating benign lesions were low (diagnostic accuracy: 47.6%; sensibility: 5.3%). Poor results were also obtained in the sub-analysis of small (mean diameter < 3 cm) and large (mean diameter > 3 cm) lesions. No differences were recorded in the type of CE pattern showed between benign and malignant peripheral pulmonary lesions. In benign lesions we observed a higher frequency of delayed CE wash-out time (WOT) > 300 s. Anyhow, a CE WOT cut-off value > 300 s showed low diagnostic accuracy (53.6%) and sensibility (16.5%) in discriminating between pneumonias and malignancies. Similar results were also obtained in the sub-analysis by lesion size. Squamous cell carcinomas showed a more delayed CE AT compared to other histopathology subtypes. However, such a difference was statistically significant with undifferentiated lung carcinomas. Conclusions. Due to an overlap of CEUS timings and patterns, dynamic CEUS parameters cannot effectively differentiate between benign and malignant peripheral pulmonary lesions. Chest CT remains the gold standard for lesion characterization and the eventual identification of other pneumonic non-subpleural localizations. Furthermore, in the case of malignancy, a chest CT is always needed for staging purposes.
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BACKGROUND: Lung cancer is the main cause of cancer-related death worldwide, and 85% of all lung tumors are non-small cell lung cancers (NSCLC). More than 60% of all lung tumors are diagnosed at an advanced stage, leading to poor prognosis. Given the growing demand for NSCLC profiling for selection of the most appropriate therapy, the acquisition of adequate tumor samples has become increasingly crucial, mostly in advanced NSCLC patients due to old age and/or comorbidities. Being a mini-invasive sampling technique, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) represents a valuable alternative to traditional transthoracic or surgical sampling in these patients, and perfoming cell block (CB) could be crucial to maximize the potential biological information. The aim of this study is to describe a monoinstitutional interprofessional experience in handling EBUS-TBNA and CB in 464 patients. METHODS: We retrospectively collected all the consecutive CBs obtained from EBUS TBNA performed between 2014 and 2021 on the lung lesions or mediastinal lymph nodes. All the CBs were handled in a standardized method. RESULTS: A total of 95.5% (448/464 samples) of adequacy for site and 92.6% (430/464) of adequacy for diagnosis were observed. Moreover, in the adenocarcinoma histotype, ALK, ROS1 and tumor proportion score (TPS) PD-L1 assessment by IHC was possible in 96% (140/146) of cases, and molecular profile was obtained in 93.8% (137/146) of cases. In the squamous cell carcinoma histotype, TPS PD-L1 assessment was possible in 81% (13/16) of cases. All four CB results obtained from carcinoma NOS were adequate for ALK, ROS1 and PD-L1 assessment and molecular profiling. All 39 metastatic samples from extra-pulmonary primary were adequate for immunohistochemical characterization and molecular profiling. Finally, reporting of the tumor sample adequacy to the clinicians took a median time of about 30 h (range: 24-80 h). CONCLUSION: Careful cytological smear management together with the handling and standardization of CB obtained from EBUS-TBNA could represent an effective method to increase the adequacy of the tumor specimen for both diagnosis and molecular profile.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/metabolismo , Broncoscopia/métodos , Carcinoma Pulmonar de Células não Pequenas/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Padrões de Referência , Estudos RetrospectivosRESUMO
(1) Background: Despite the high accuracy of CT-guided transthoracic biopsy for diagnosis of pulmonary lesions, in a certain amount of cases biopsy results may indicate the presence of nonspecific findings or insufficient material. We aimed to investigate the effectiveness of CT-guided transthoracic biopsy of pulmonary lesions in providing a specific diagnosis and to analyze the variables affecting biopsy results. (2) Methods: In this retrospective study, a total of 170 patients undergoing 183 CT-guided transthoracic biopsies of pulmonary lesions were included. The clinical, radiological and pathological data were reviewed to classify biopsy results as diagnostic or nondiagnostic and to identify which variables were associated with the two groups. (3) Results: The biopsy results were diagnostic in 150 cases (82.0%), of which 131 (87.3%) positive for malignancy and 19 (12.7%) with specific benign lesions, and nondiagnostic in 33 cases (18.0%). Twenty-two of the thirty-three (66.7%) nondiagnostic cases were finally determined as malignancies and eleven (33.3%) as benign lesions. In the diagnostic group, all the 131 biopsies positive for malignancy were confirmed to be malignant at final diagnosis (87.3%); of 19 biopsies with specific benign lesions, 13 cases were confirmed to be benign (8.7%), whereas six cases had a final diagnosis of malignancy (4%). Multivariate analysis showed increased risk of nondiagnostic biopsy for lesions ≤ 20 mm (p = 0.006) and lesions with final diagnosis of benignity (p = 0.001). (4) Conclusions: CT-guided transthoracic lung biopsy is an effective technique for the specific diagnosis of pulmonary lesions, with a relatively acceptable proportion of nondiagnostic cases. Small lesion size and final benign diagnosis are risk factors for nondiagnostic biopsy results.
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OBJECTIVE: The state-trait nature of alexithymia is not fully resolved. The aim of this article was to evaluate the temporal stability of alexithymia in cancer patients after psychological intervention. DESIGN: Absolute and relative stability of alexithymia was evaluated in 104 cancer patients who received multicomponent psychological treatment or usual medical care. RESULTS: Alexithymia scores significantly decreased in treated patients and increased in the control group, thus showing that the lack of absolute stability (i.e., the change of personality scores over time) likely was because of the effect of the treatment versus the control condition. The relative stability (i.e., the extent to which the inter-individual differences remain the same over time) of alexithymia after 6 months was, however, demonstrated with multiple regressions, after controlling for anxiety, depression, and cancer-related pain. CONCLUSIONS: This study confirms the relative stability of alexithymia and that the lack of absolute stability of the construct is influenced by psychological intervention in cancer patients.
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Sintomas Afetivos/reabilitação , Neoplasias/psicologia , Psicoterapia , Estudos de Casos e Controles , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Dor/prevenção & controle , Psicoterapia/métodos , Qualidade de Vida , Análise de RegressãoRESUMO
Clinical manifestations accompanying respiratory failure with insidious and rapidly progressive onset are often non-specific. Symptoms such as a cough, dyspnea, and fever are common to a large number of inflammatory, infectious, or neoplastic diseases. During the COVID-19 pandemic it is essential to limit the use of hospital services and inappropriate diagnostic techniques. A particular radiological pattern can orient the clinical and laboratory scenario and guide the diagnostic workup. A 58-year-old woman was admitted to our COVID-19 unit for suspected coronavirus infection. She was complaining of worsening dyspnea, tachycardia, and low grade fever. A chest X-ray showed diffuse, alveolar, and interstitial lung involvement with micronodules tending to coalescence. This radiographic pattern known as "galaxy sign", consistent with diffuse, coalescing nodular miliary pulmonary involvement, simulating a non-specific alveolar opacification of the lungs is typical of a few pneumological differential diagnoses, represented by sarcoidosis, tuberculosis, pneumoconiosis, and metastatic lesions, and virtually excludes an interstitial viral pneumonitis. The use of endoscopic techniques can, in such cases, confirm the clinical suspicion for initiating appropriate targeted therapies.
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INTRODUCTION: Fusions in neuregulin 1 (NRG1) and neuregulin 2 (NRG2) genes are molecular features of non-small cell lung cancer (NSCLC). These rearrangements enhance ectopic expression of the NRG/ErbB receptor-ligand and induce the triggering of downstream pathways. Evidence suggests the involvement of the NRG1/ErbB3 axis deregulation in the progression and treatment resistance of NSCLC cancer (NSCLC) and that NRG1 fusions are prognostic/predictive markers for targeted therapy. AREAS COVERED: Biological and prognostic/predictive value of NRG1 and NRG2 fusions in NSCLC and their related cellular pathways are described and discussed. Publications in English language, peer-reviewed, high-quality international journals were identified on PubMed, as well as scientific official sites were used to update the international clinical trials progress. EXPERT OPINION: NRG1 and NRG2 fusions should be considered as novel markers for biological therapy targeting ErbB2/ErbB3. There is evidence for the involvement of the NRG1/ErbB3 axis deregulation in cancer stem cell phenotype, tumor progression, and resistance to NSCLC therapy. Neuregulin fusions are very complex, hence many question marks must be tackled before translating these molecular lesions into clinical practice. Biology, and aggressiveness of the NRG1 and NRG2 fusions warrant further investigations.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neuregulina-1/genética , Neuregulina-1/metabolismo , Neuregulina-1/uso terapêuticoRESUMO
In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations.
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Pulmonary carcinoids combined with a non-neuroendocrine component have rarely been described, and this histological subtype is not included as a specific entity in the current World Health Organization classification of pulmonary neoplasms. Here, we described the molecular and histological features of two rare cases of mixed lung neoplasms, composed of atypical carcinoid and adenocarcinoma. The targeted next-generation sequencing analysis covering single nucleotide variations, copy number variations, and transcript fusions in a total of 161 cancer genes of the two different tumor components shows a similar molecular profile of shared and private gene mutations. These findings suggest their monoclonal origin from a transformed stem/progenitor tumor cell, which acquires a divergent differentiation during its development and progression and accumulates novel, specific mutations.
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No well-established prognostic or predictive molecular markers of small-cell lung cancer (SCLC) are currently available; therefore, all patients receive standard treatment. Adequate quantities and quality of tissue samples are frequently unavailable to perform a molecular analysis of SCLC, which appears more heterogeneous and dynamic than expected. The implementation of techniques to study circulating tumor cells could offer a suitable alternative to expand the knowledge of the molecular basis of a tumor. In this context, the advantage of SCLC circulating cells to express some specific markers to be explored in blood as circulating transcripts could offer a great opportunity in distinguishing and managing different SCLC phenotypes. Here, we present a summary of published data and new findings about the detection methods and potential application of a group of neuroendocrine related transcripts in the peripheral blood of SCLC patients. In the era of new treatments, easy and rapid detection of informative biomarkers in blood warrants further investigation, since it represents an important option to obtain essential information for disease monitoring and/or better treatment choices.
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(1) Background: The aim of this study was to conduct a prospective analysis on the diagnostic accuracy of transthoracic ultrasound-guided percutaneous needle biopsy (TUS-PNB) for the histological assessment of peripheral lung lesions and to assess the performance of transthoracic ultrasound (TUS) examination vs. chest CT (gold standard) in the differentiation between malignant and benign peripheral lung lesions. (2) Methods: A total of 961 consecutive patients with subpleural pulmonary lesions were enrolled. All the patients received a CT scan with contrast; 762 patients underwent TUS-PTNB for suspicion of malignancy, and the remaining 199 enrolled patients underwent only TUS examination as a part of routine follow-up for known non-malignant subpleural consolidations. (3) Results: Among the 762 TUS-guided biopsies, there were 627 (82.28%) malignant lesions, 82 (10.76%) benign lesions, and 53 (6.96%) indeterminate lesions. The overall diagnostic accuracy was 93.04%. The rates of pneumothorax not requiring chest-tube insertion and self-limited hemoptysis were 0.79 and 0.26%, respectively. Patients were divided into two groups based on the benign or malignant nature of the subpleural consolidations. On TUS, both malignant and benign lesions showed mostly irregular margins and a hypoechoic pattern, but no differences were assessed in terms of sonographic margins and pattern between the two groups. There was poor agreement between TUS and chest CT in assessing air bronchograms and necrotic areas. The only finding in the detection of which TUS showed superiority compared to chest-CT was pleural effusion. (4) Conclusions: TUS-PNB was confirmed to be an effective and safe diagnostic method for peripheral pulmonary consolidation, but their sonographic pattern did not allow to rule out a malignant nature. A pre-operative evaluation on CT images, combined with the possibility of performing additional immunohistochemical and cytological investigations and the experience of the medical staff, may improve the diagnostic yield of TUS-guided biopsies.
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BACKGROUND: The deeper knowledge of non-small-cell lung cancer (NSCLC) biology and the discovery of driver molecular alterations have opened the era of precision medicine in lung oncology, thus significantly revolutionizing the diagnostic and therapeutic approach to NSCLC. In Italy, however, molecular assessment remains heterogeneous across the country, and numbers of patients accessing personalized treatments remain relatively low. Nationwide programs have demonstrated that the creation of consortia represent a successful strategy to increase the number of patients with a molecular classification. PATIENTS AND METHODS: The Alliance Against Cancer (ACC), a network of 25 Italian Research Institutes, has developed a targeted sequencing panel for the detection of genomic alterations in 182 genes in patients with a diagnosis of NSCLC (ACC lung panel). One thousand metastatic NSCLC patients will be enrolled onto a prospective trial designed to measure the sensitivity and specificity of the ACC lung panel as a tool for molecular screening compared to standard methods. RESULTS AND CONCLUSION: The ongoing trial is part of a nationwide strategy of ACC to develop infrastructures and improve competences to make the Italian research institutes independent for genomic profiling of cancer patients.
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Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Detecção Precoce de Câncer , Genômica , Humanos , Itália , Neoplasias Pulmonares/genética , Programas de Rastreamento/métodos , Medicina de Precisão/métodos , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
Tumor lysis syndrome has been observed in patients with bulky, treatment-sensitive tumors, in particular hematological malignancies, especially after medical treatment (chemotherapy, corticosteroids, radiation, hormonal agents, and biological response modifiers). Tumor lysis syndrome has been observed also in solid malignancies and it very rarely occurs spontaneously. Tumor lysis syndrome-associated metabolic abnormalities include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and uremia. Severe hypoglycemia is another rare metabolic disorder, uncommonly associated with solid malignancies. The case described here is peculiar for the abrupt onset of these two rare conditions in a patient with a metastatic germ cell tumor.
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Coriocarcinoma/complicações , Hipoglicemia/etiologia , Neoplasias Embrionárias de Células Germinativas/complicações , Neoplasias Testiculares/complicações , Síndrome de Lise Tumoral/etiologia , Doença Aguda , Adulto , Biomarcadores Tumorais/análise , Coriocarcinoma/sangue , Coriocarcinoma/química , Coriocarcinoma/patologia , Humanos , Hipoglicemia/sangue , Imuno-Histoquímica , Queratinas/análise , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Neoplasias Embrionárias de Células Germinativas/sangue , Neoplasias Embrionárias de Células Germinativas/química , Neoplasias Embrionárias de Células Germinativas/patologia , Lactogênio Placentário/análise , Índice de Gravidade de Doença , Neoplasias Testiculares/sangue , Neoplasias Testiculares/química , Neoplasias Testiculares/patologia , Síndrome de Lise Tumoral/sangue , Vimentina/análise , alfa-Fetoproteínas/análiseRESUMO
Thymoma is the most frequent neoplasm arising in the anterior mediastum. It usually presents as an enlarged central mass. In the literature, multiple thymoma is described as an unusual finding; rare variants have also been described, like the signet ring-like cell variant. Evidence of co-existence of signet ring-like cells and lymphocytes in small biopsies from nodular mediastinal lesions can lead to a diagnosis of metastatic carcinoma, mostly at frozen sections. Thymoma and pulmonary carcinoma are very rarely associated neoplasms. We present a case of two mediastinal lesions discovered during pulmonary carcinoma staging. At frozen section, a diagnosis of 'epithelioid proliferation associated to lymphoid tissue' was advanced on a sample of nodular lesions and of 'carcinoma' on pulmonary biopsy. Double AB Type Thymoma with a signet ring cell-like component, synchronous to pulmonary adenocarcinoma, was the diagnosis made on formalin fixed-paraffin embedded samples. Reporting the coexistence of these two entities can help pathologists and surgeons to establish the best management of similar patients.
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INTRODUCTION: First- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, icotinib, and afatinib are the standard-of-care for first-line therapy of non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations. Unfortunately, after initial activity of an average 9-13 months, disease progression has been reported in the majority of patients. In about 50% of cases the progression is due to the onset of the T790M mutation in exon 20 of the EGFR gene. Third-generation EGFR-TKIs targeting this mutation were investigated, with osimertinib the only reaching clinical practice. Areas covered: A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question addressing osimertinib, was undertaken. Expert opinion: Osimertinib is the standard-of-care for EGFR-mutated patients progressing to first-line EGFR-TKIs due to the acquired EGFR T790M mutation. Results from the head-to-head first-line trial comparing osimertinib versus gefitinib or erlotinib in activating EGFR mutations might change the front-line approach. Osimertinib in combination regimens, such as immunotherapy, and in adjuvant setting are ongoing. Thus, the strategic approach for the management of EGFR-mutated NSCLC patients will change further in the next few years.