Bronchoscopically-visible massive central airway cancer cavitation is associated with metastatic disease, lack of actionable mutations and poor prognosis: a case series.

Cavitating lung tumors occur in approximately 10-15% of the patients, are more commonly associated with squamous histology, and are typically located in the lung parenchyma. Herein we describe an exceedingly rare series of 5 patients, 4 of whom treatment-naïve, whose tumor caused the disruption of the normal airway anatomy at the level of lobar or segmental bronchi, leading to the formation of an endoscopically-visible cavity which ended up in the lung parenchyma or even into the pleural space. Sex (3 males, 2 females), smoking habit (2 never smokers, 2 former smokers, 1 current smoker), and histology (3 adenocarcinoma, 2 squamous cell carcinoma) were heterogeneous, but the 4 patients treatment-naïve presented with metastatic disease, poor ECOG performance status, similar clinical complaints of long duration, and lack of actionable mutations. The only patient who exhibited a meaningful response to treatment had the lowest symptoms' duration, the smallest size of the cavitated mass, and the best performance status at the time of diagnosis. This series provides the first comprehensive description of a rare presentation of lung cancer characterized by similar clinical complaints, delayed diagnosis and poor prognosis.

Diagnosis and Molecular Profiling of Lung Cancer by Percutaneous Ultrasound-Guided Biopsy of Superficial Metastatic Sites Is Safe and Highly Effective.

BACKGROUND: Diagnosis, staging, and molecular profiling of lung cancer are mostly carried out with bronchoscopy or CT-guided aspiration/biopsy. However, patients with locally advanced or advanced disease often harbor "superficial" metastases for which a percutaneous, ultrasound-assisted needle aspiration/biopsy (US-NAB) might represent an equally effective yet less invasive and costly alternative. PATIENTS AND METHODS: We reviewed a prospectively collected database of consecutive patients with known/suspected lung cancer who underwent a US-NAB of a suspected "superficial" metastasis. Cancer genotyping was carried out with next-generation sequencing using the Oncomine™ Focus DNA and RNA fusion panels. PD-L1 immunohistochemistry was performed with the SP263 antibody. Feasibility, diagnostic yield for tissue diagnosis, sensitivity for malignancy, diagnostic yield for the molecular profiling, and complications were the study endpoints. RESULTS: A total of 98 lesions were evaluated, and 93 were biopsied (95% feasibility). The spectrum of sampled sites included lymph nodes (63 patients), bone (11), subcutaneous tissue (8), muscle (7), and the pleura (4). The diagnostic yield for a tissue diagnosis was 93% (91/98). US-NAB correctly identified 85 of the 87 patients finally diagnosed with malignancy (98% sensitivity). Cancer genotyping and PDL1 testing were successfully completed in 41/42 patients (98%) and in 40/50 patients (80%) for whom these tests were requested, respectively. No complications were observed. CONCLUSION: US-NAB of "superficial" metastasis of lung cancer is safe and is associated with high success for diagnosis and molecular profiling. In this clinical setting, using US-NAB as a first-step technique would significantly limit the use of more invasive and costly diagnostic procedures.

Interobserver agreement between pathologist, pulmonologist and molecular pathologist to estimate the tumour burden in rapid on-site evaluation smears from endosonography and guided bronchoscopy.

OBJECTIVE: A growing number of studies have suggested that non-pathologists can reliably assess the adequacy and malignancy in rapid on-site evaluation (ROSE) smears prepared during endoscopic sampling procedures. However, no study has verified whether they can also consistently estimate the tumour burden, which is critical for the molecular profiling of lung cancer. We aimed to assess the interobserver agreement (IOA) between a pathologist, a pulmonologist (previously trained in lung and lymph node cytopathology) and a molecular pathologist for the tumour burden in ROSE smears. METHODS: The ROSE smears of consecutive patients with suspected lung cancer undergoing endosonography or guided bronchoscopy were assessed independently by a pathologist, a pulmonologist and a molecular pathologist (gold standard). The IOA for the tumour burden, assessed through k-statistics, was the primary outcome. RESULTS: A total of 322 ROSE smears obtained from 162 patients were evaluated. The IOA between the molecular pathologist and pulmonologist was very good (moderate to substantial), although slightly inferior to the IOA between the molecular pathologist and pathologist in the whole slide set (k: 0.707, 95% confidence interval [CI]: 0.677-0.739 vs 0.793, 95% CI: 0.762-0.815), as well as in smears prepared from lymphadenopathy (k: 0.783, 95% CI: 0.760-0.855 vs 0.827, 95% CI: 0.728-0.892) or from pulmonary nodules/masses (k: 0.558, 95% CI: 0.416-0.686 vs 0.715, 95% CI: 0.621-0.767). CONCLUSIONS: A professionally trained pulmonologist can reliably estimate the tumour burden in bronchoscopically derived ROSE smears, especially in the setting of lymphadenopathy. This can be particularly useful in institutions where a cytopathologist is not available regularly.

A Trained Pulmonologist Can Reliably Assess Endosonography-Derived Lymph Node Samples during Rapid On-Site Evaluation.

BACKGROUND: The widespread use of rapid on-site evaluation is hampered by constraints related to time and resources, inadequate reimbursement, and evidence from randomized trials that show a lack of increase in diagnostic yield and specimen adequacy associated with its usage. OBJECTIVE: We aimed to verify whether a pulmonologist can assess endosonography-derived lymph node samples after a comprehensive and reproducible training provided by a specialist pathologist. METHODS: Prospective, observational trial structured in three phases. In the first (training) phase, a pathologist critically evaluated the smears from 150 archival endosonography cases with a pulmonologist. In the second (test) phase, the pulmonologist was asked to assess 50 archival endosonography-derived samples. In the last (real-life) phase, the pulmonologist classified the samples from 200 patients during the endosonography. The overall agreement between pulmonologist and pathologist (gold standard), assessed through κ-statistics, was the primary outcome. The agreement for the identification of specific cytological categories was the secondary outcome. RESULTS: The overallagreement between pulmonologist and pathologist was 84% (κ0.765, 95% CI 0.732-0.826) in the test phase and 89.7% (κ 0.844, 95% CI 0.799-0.881) in the real-life phase. The agreement for specific cytological categories was 92.7% (95% CI 0.824-0.980) for inadequate samples, 90.3% (95% CI 84.5-94.5%) for reactive lymphadenopathies, 90.5% (95% CI 0.845-0.946) for malignancy, and 73% (95% CI 0.515-0.897) for granulomatous samples. CONCLUSIONS: A trained pulmonologist can reliably assess adequacy and malignancy for endosonography-derived samples, which could be useful in institutions where a cytopathologist/cytotechnician is not available regularly.

Intrathoracic Lymph Node Microcalcifications are Associated With a High Prevalence of Malignancy and Anaplastic Lymphoma Kinase Rearrangement: The "Calce" Study.

BACKGROUND: Microcalcifications are acknowledged as a malignancy risk factor in multiple cancers. However, the prevalence and association of intrathoracic lymph node (ILN) calcifications with malignancy remain unexplored. METHODS: In this cross-sectional study, we enrolled patients with known/suspected malignancy and an indication for endosonography for diagnosis or ILN staging. We assessed the prevalence and pattern of calcified ILNs and the prevalence of malignancy in ILNs with and without calcifications. In addition, we evaluated the genomic profile and PD-L1 expression in lung cancer patients, stratifying them based on the presence or absence of ILN calcifications. RESULTS: A total of 571 ILNs were sampled in 352 patients. Calcifications were detected in 85 (24.1%) patients and in 94 (16.5%) ILNs, with microcalcifications (78/94, 83%) being the predominant type. Compared with ILNs without calcifications (214/477, 44.9%), the prevalence of malignancy was higher in ILNs with microcalcifications (73/78, 93.6%; P<0.0001) but not in those with macrocalcifications (7/16, 43.7%; P=0.93). In patients with lung cancer, the high prevalence of metastatic involvement in ILNs displaying microcalcifications was independent of lymph node size (< or >1 cm) and the clinical stage (advanced disease; cN2/N3 disease; cN0/N1 disease). The anaplastic lymphoma kinase (ALK) rearrangement was significantly more prevalent in patients with than in those without calcified ILNs (17.4% vs. 1.7%, P<0.001), and all of them exhibited microcalcifications. CONCLUSION: ILN microcalcifications are common in patients undergoing endosonography for suspected malignancy, and they are associated with a high prevalence of metastatic involvement and ALK rearrangement.

High-Definition Videobronchoscopy for the Diagnosis of Airway Involvement in Sarcoidosis: The Enhance Sarcoidosis Multicenter Study.

BACKGROUND: The ability of high-definition (HD) videobronchoscopy to detect airway involvement in sarcoidosis has not been evaluated previously. RESEARCH QUESTION: What is the role of HD videobronchoscopy in the identification of sarcoidosis-associated airway abnormalities (AAs)? What are the patterns of AAs more commonly observed and more frequently associated with the detection of granulomas in endobronchial biopsy (EBB)? STUDY DESIGN AND METHODS: In this prospective international multicenter cohort study, consecutive patients with suspected sarcoidosis underwent airway inspection with an HD videobronchoscope and EBB using a standardized workflow. AAs were classified according to six patterns defined a priori: nodularity, cobblestoning, thickening, plaque, increased vascularity, and miscellaneous. We assessed diagnostic yield of EBB, prevalence of AAs, and interobserver agreement for different patterns of AAs. RESULTS: AAs were identified in 64 of 134 patients with sarcoidosis (47.8%), with nodularity (n = 23 [17.2%]), plaque (n = 19 [14.2%]), and increased vascularity (n = 19 [14.2%]) being the most prevalent. The diagnostic yield of EBB was 36.6%. AAs were significantly more prevalent in patients with than in those without nonnecrotizing granulomas on EBB (67.4% vs 36.5%; P = .001). Likewise, parenchymal disease on CT scan imaging was significantly more common in patients with than in those without nonnecrotizing granulomas on EBB (79.6% vs 54.1%; P = .003). On a per-lesion analysis, nonnecrotizing granulomas were seen especially in EBB samples obtained from areas of cobblestoning (9/10 [90%]) and nodularity (17/29 [58.6%]). The overall diagnostic yield of random EBB was low (31/134 [23.1%]). The interobserver agreement for the different patterns of AA was fair (Fleiss κ = 0.34). INTERPRETATION: In a population with a large prevalence of White Europeans, HD videobronchoscopy detected AAs in approximately one-half of patients with sarcoidosis. The diagnostic yield of EBB was higher in patients with parenchymal involvement on CT scan imaging and in those with AAs, especially if manifesting as cobblestoning and nodularity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT4743596; URL: www. CLINICALTRIALS: gov.

Thirty-Day Complications, Unplanned Hospital Encounters, and Mortality after Endosonography and/or Guided Bronchoscopy: A Prospective Study.

BACKGROUND AND OBJECTIVE: Limited data exist regarding the adverse events of advanced diagnostic bronchoscopy, with most of the available information derived from retrospective datasets that primarily focus on early complications. METHODS: We conducted a 15-month prospective cohort study among consecutive patients undergoing endosonography and/or guided bronchoscopy under general anesthesia. We evaluated the 30-day incidence of severe complications, any complication, unplanned hospital encounters, and deaths. Additionally, we analyzed the time of onset (immediate, within 1 h of the procedure; early, 1 h-24 h; late, 24 h-30 days) and identified risk factors associated with these events. RESULTS: Thirty-day data were available for 697 out of 701 (99.4%) enrolled patients, with 85.6% having suspected malignancy and multiple comorbidities (median Charlson Comorbidity Index (IQR): 4 (2-5)). Severe complications occurred in only 17 (2.4%) patients, but among them, 10 (58.8%) had unplanned hospital encounters and 2 (11.7%) died within 30 days. A significant proportion of procedure-related severe complications (8/17, 47.1%); unplanned hospital encounters (8/11, 72.7%); and the two deaths occurred days or weeks after the procedure. Low-dose attenuation in the biopsy site on computed tomography was independently associated with any complication (OR: 1.87; 95% CI 1.13-3.09); unplanned hospital encounters (OR: 2.17; 95% CI 1.10-4.30); and mortality (OR: 4.19; 95% CI 1.74-10.11). CONCLUSIONS: Severe complications arising from endosonography and guided bronchoscopy, although uncommon, have significant clinical consequences. A substantial proportion of adverse events occur days after the procedure, potentially going unnoticed and exerting a negative clinical impact if a proactive surveillance program is not implemented.

Diffuse lung disease in neurofibromatosis.

Prevalence, characteristics and the very existence of neurofibromatosis-associated diffuse lung disease remain unclear, mostly because the few studies that looked at pulmonary involvement in such patients used chest X-ray as diagnostic mean. We report on the clinical, functional and HRCT findings in a patient with neurofibromatosis-associated diffuse lung disease and provide a short literature review.

Ultrasound-Guided Needle Aspiration Biopsy of Superficial Metastasis of Lung Cancer with and without Rapid On-Site Evaluation: A Randomized Trial.

BACKGROUND AND OBJECTIVE: Studies which evaluated the role of an ultrasound-guided needle aspiration biopsy (US-NAB) of metastases from lung cancer located in "superficial" organs/tissues are scant, and none of them assessed the possible impact of rapid on-site evaluation (ROSE) on diagnostic accuracy and safety outcomes. METHODS: Consecutive patients with suspected superficial metastases from lung cancer were randomized 1:1 to US-NAB without (US-NAB group) or with ROSE (ROSE group). The diagnostic yield for a tissue diagnosis was the primary outcome. Secondary outcomes included the diagnostic yield for cancer genotyping, the diagnostic yield for PD-L1 testing, and safety. RESULTS: During the study period, 136 patients were randomized to receive an US-NAB with (n = 68) or without ROSE (n = 68). We found no significant differences between the ROSE group and the US-NAB group in terms of the diagnostic yields for tissue diagnosis (94.1% vs. 97%, respectively; p = 0.68), cancer genotyping (88% vs. 91.8%, respectively; p = 0.56), and PD-L1 testing (93.5% vs. 90.6%, respectively; p = 0.60). Compared to the diagnostic US-NAB procedures, the non-diagnostic procedures were characterized by less common use of a cutting needle (66.6% vs. 96.9%, respectively; p = 0.0004) and less common retrieval of a tissue core (37.5% vs. 98.5%; p = 0.0001). Only one adverse event (vasovagal syncope) was recorded. CONCLUSION: US-NAB of superficial metastases is safe and has an excellent diagnostic success regardless of the availability of ROSE. These findings provide a strong rationale for using US-NAB as the first-step method for tissue acquisition whenever a suspected superficial metastatic lesion is identified in patients with suspected lung cancer.

Performance characteristics and predictors of yield from transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions.

BACKGROUND AND OBJECTIVE: Transbronchial needle aspiration (TBNA) is useful for diagnosing peripheral pulmonary lesions (PPL). However, TBNA is largely underused and the variables that may be related to its diagnostic usefulness have not been specifically studied. The aim of the present study was to evaluate the performance characteristics and predictors of yield from TBNA of PPL, and to compare the performance characteristics of different bronchoscopic sampling methods. METHODS: Consecutive patients with PPL were prospectively enrolled, and during the same examination, TBNA, transbronchial lung biopsy (TBLB) and bronchial washing (BW) were performed. RESULTS: Two hundred and eighteen PPL in 218 patients were sampled. TBNA was more sensitive (65%) than either TBLB (45%, P<0.001) or BW (22%, P<0.001). TBNA was the only diagnostic procedure in 42/196 patients (21%) with malignant lesions, and was more likely to be the only diagnostic procedure for lesions lacking (23/85 patients, 27%) than for lesions with the bronchus sign (19/111 patients, 17%). In multivariate analysis, a lesion size >2cm, malignancy and location in the middle lobe were independent predictors of a positive TBNA result. CONCLUSIONS: TBNA is the single best contributor to the success of bronchoscopy in the diagnosis of PPLs, and should be routinely used especially in the presence of lesions lacking the bronchus sign. Lesion size of > 2cm, location in the middle lobe, and malignant nature are strong predictors of a positive TBNA result.

Pattern of cancer patient referral and organisational model of an interventional pulmonology programme during the COVID-19 pandemic.

An interventional pulmonary programme can be carried out safely for both cancer patients and HCWs during the #COVID19 pandemic. However, a worrisome reduction of new cancer patient referral occurs during periods of high community spread of the virus. https://bit.ly/2PRWNXo.

Endobronchial ultrasound for T4 staging in patients with resectable NSCLC.

BACKGROUND: In lung cancer patients, accurate assessment of mediastinal and vascular tumor invasion (stage T4) is crucial for optimal treatment allocation and to prevent unnecessary thoracotomies. We assessed the diagnostic accuracy of linear endobronchial ultrasound (EBUS) for T4-status in patients with centrally located lung cancer. METHODS: This is a retrospective study among consecutive patients who underwent EBUS for diagnosis and staging of lung cancer in four hospitals in The Netherlands (Amsterdam, Leiden), Italy (Bologna) and Poland (Zakopane) between 04-2012 and 04-2019. Patients were included if the primary tumor was detected by EBUS and subsequent surgical-pathological staging was performed, which served as the reference standard. T4-status was extracted from EBUS and pathology reports. Chest CT's were re-reviewed for T4-status. RESULTS: 104 patients with lung cancer in whom EBUS detected the primary tumour, and who underwent subsequent surgical-pathological staging were included. 36 patients (35 %) had T4-status, based on vascular (n = 17), mediastinal (n = 15), both vascular and mediastinal (n = 3), or oesophageal invasion (n = 1). For EBUS, sensitivity, specificity, PPV and NPV for T4-status were (n = 104): 63.9 % (95 %CI 46.2-79.2 %), 92.6 % (83.7-97.6 %), 82.1 % (65.6-91.7 %), and 82.9 % (75.7-88.2 %), respectively. For chest CT (n = 72): 61.5 % (95 %CI 40.6-79.8 %), 37.0 % (23.2-52.5 %), 35.6 % (27.5-44.6 %), and 63.0 % (47.9-75.9 %), respectively. When combining CT and EBUS with concordant T4 status (n = 33): 90.9 % (95 %CI 58.7-99.8 %), 77.3 % (54.6-92.20 %), 66.7 % (47.5-81.6 %), and 94.4 % (721-99.1%), respectively. CONCLUSION: Both EBUS and CT alone are inaccurate for assessing T4-status as standalone test. However, combining a negative EBUS with a negative CT may rule out T4-status with high certainty.

Pulmonary adenocarcinoma with psammoma bodies is associated with a specific endobronchial ultrasound pattern and a high prevalence of actionable driver mutations.

INTRODUCTION: Pulmonary adenocarcinoma with psammoma bodies (PAPBs) is a rare histological variant whose association with a high prevalence of targetable mutations has been suggested by scant literature reports describing small series. We aim to describe the endobronchial ultrasound (EBUS) pattern and the molecular profile by next-generation sequencing of an Italian series of patients with PAPBs. MATERIAL AND METHODS: Over a 8-year period (2012-2019), we identified 15 patients with a very uncommon endobronchial ultrasound (EBUS) heterogeneity pattern characterized by the presence of multiple to countless, punctate non-shadowing foci ("starry sky" sign) which were not evident at CT and corresponded to psammoma bodies at pathological examination. The clinical, radiological, pathological and molecular findings of these patients were retrieved and analyzed. RESULTS: Pathological examination of the EBUS-TBNA specimens revealed malignancy (12 pulmonary adenocarcinoma, 2 breast carcinoma, 1 colonic carcinoma) and showed the presence of psammoma bodies in all of the 15 patients with the starry sky sign. Among the 12 patients with pulmonary adenocarcinoma with psammoma bodies, female sex (8/12, 66.7 %) and never-smoking habit (6/12, 50 %) were prevalent. Molecular tumor profiling using the Oncomine™ Focus DNA and RNA fusion panels was successfully performed in 11/12 patients and revealed 10 genetic alterations (BRAF mutation, 4; EGFR mutation, 2; ALK rearrangement, RET rearrangement, PIK3CA mutation, CDK4 amplification 1) in 7 patients (63.6 %). CONCLUSION: The present series suggests that pulmonary adenocarcinoma with psammoma bodies is associated with a readily identifiable EBUS pattern and with a high prevalence of different, often uncommon and actionable, driver mutations.

Reliability of programmed death ligand 1 (PD-L1) tumor proportion score (TPS) on cytological smears in advanced non-small cell lung cancer: a prospective validation study.

INTRODUCTION: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assessment is mandatory for the single agent pembrolizumab treatment of patients with advanced non-small cell lung cancer (NSCLC). PD-L1 testing has been validated and is currently certified only on formalin-fixed paraffin-embedded materials but not on cytological smears. Unfortunately, a significant proportion of patients, having only cytological material available, cannot be tested for PD-L1 and treated with pembrolizumab. In this study, we aimed to validate PD-L1 IHC on cytological smears prospectively by comparing clone SP263 staining in 150 paired histological samples and cytological smears of NSCLC patients. METHODS: We prospectively enrolled 150 consecutive advanced NSCLC patients. The clone SP263 was selected as, in a previous study of our group, it showed higher accuracy compared with clones 28-8 and 22-C3, with good cyto-histological agreement using a cut-off of 50%. For cyto-histological concordance, we calculated the kappa coefficient using two different cut-offs according to the percentage of PD-L1 positive neoplastic cells (<1%, 1-49% and ⩾50%; <50%, ⩾50%). RESULTS: The overall agreement between histological samples and cytological smears was moderate (kappa = 0.537). However, when the cyto-histological concordance was calculated using the cut-off of 50%, the agreement was good (kappa = 0.740). With the same cut-off, and assuming as gold-standard the results on formalin-fixed paraffin-embedded materials, PD-L1 evaluation on smears showed specificity and negative predictive values of 98.1% and 93.9%, respectively. CONCLUSION: Cytological smears can be used in routine clinical practice for PD-L1 assessment with a cut-off of 50%, expanding the potential pool of NSCLC patients as candidates for first-line single agent pembrolizumab therapy.

"Melting Lymph Node Sign": The Endobronchial Ultrasound Pattern Of Cystic Mediastinal Nodal Metastases.

Cystic change in metastatic lymph nodes occurs in certain types of tumors (ie, papillary thyroid carcinoma and squamous cell carcinoma of the Waldeyer's ring) and it is usually observed in the head and neck region. We report on a series of 6 patients with mediastinal metastasis from lung cancer in whom the endobronchial ultrasound showed that most of the lymph node tissue had "melted," leading to the formation of a single, anechoic, avascular cavity. Besides the unique endobronchial ultrasound pattern, we describe the imaging and pathology findings of this unusual presentation of malignant mediastinal lymphadenopathy to facilitate its recognition.