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• Spread through air spaces is suggested to be invasion way of lung parenchyma. • Spread through air spaces has been described around lung neuroendocrine neoplasms. • Spread through air spaces may be made up by hyperplastic neuroendocrine cells. • Spread through air spaces is likely to be an ex vivo artifact due to tissue manipulation. Spread through air spaces (STAS) is a recently proposed invasion way of lung cancer, including neuroendocrine (NE) neoplasms. However, if this phenomenon is a real one or an artifact while manipulating lung specimens, it is still matter of debate. Three consecutive patients with newly diagnosed diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) were reviewed for STAS. In well-fixed lung specimens, DIPNECH was seen to coexist with atypical carcinoid, bifocal typical carcinoid and adenocarcinoma in the three patients, respectively. While STAS was not observed at the growing edges of tumors, a few freely-floating aggregates of hyperplastic NE cells within air spaces were noticed to emanate from foci of NE hyperplasia and tumorlets and in intimate association with normal bronchiolar cells and erythrocytes to denote artifactual derivation upon tissue manipulation. Traveling of hyperplastic NE cells through air spaces is likely to artifactually occur via knife, surgeon or other way, thus challenging invasion by STAS. [ABSTRACT FROM AUTHOR]

Emerging studies on radiologic findings in patients with coronavirus disease 2019 (COVID-19) report a high incidence of bilateral lung involvement, with ground-glass opacities imaging being the most common pattern on computed tomography. Cystic lesions, such as pneumatoceles, are rare, although they may occur in 10% of cases. Cyst formation may be explained by a focal pulmonary trauma caused by mechanical ventilation or infection-related damage to the alveolar walls leading to pneumatoceles. The superinfection of pneumatoceles is a potential life-threatening condition for which no standardized therapeutic algorithm has been accepted. We report a case of a COVID-19 patient successfully treated by lung resections for infected pneumatoceles. [ABSTRACT FROM AUTHOR]

Large cell carcinoma (LCC) is a merely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer (SCLC), adenocarcinoma (ADC) or squamous cell carcinoma (SQC). This diagnosis is allowed on surgical specimens only, whereas its counterpart in biopsy/cytology samples is non-small-cell lung carcinoma (NSCLC), not otherwise specified (NOS). Although these two terms do not fulfill the same concept, they can be interchangeable synonyms at the clinical level, reflecting, in different ways, the inability to define a specific subtype. Immunohistochemistry (IHC), next generation sequencing (NGS) analysis and, historically, electron microscopy have been unveiling diverse cell differentiation lineages in LCC, resulting in LCC-favor ADC, LCC-favor SQC and LCC-favor large-cell neuroendocrine carcinoma (LCNEC), the latter hopefully to be included into the neuroendocrine tumor (NET) group in the future. Paradoxically, however, the interpretation issues of LCC/NSCLC-NOS are not diminishing, but even increasing albeight an accurate diagnosis is oncologically required and crucial. Also, rare LCC/NSCLC-NOS cases exhibiting null/unclear phenotype, are difficult to classify, and this terminology could be maintained for the sake of classification (basically these tumors are serendipitous ADC, as also confirmed by the lack of p40). In this review article, seven relevant issues to LCC have been addressed by using a question–answer methodology, with final key points discussing major interpretation issues. In conclusion, most LCC/NSCLC-NOS may be eventually re-classified and addressed by exploiting IHC and/or molecular testing to satisfy the criteria of precision medicine (the right drug, to the right patient, at the right time). [ABSTRACT FROM AUTHOR]

Lung neuroendocrine (NE) tumors consist of four histologic subtypes, which are usually classified based on a three-tiered prognostic scheme. They are typical carcinoid (TC) as low-grade malignant tumors, atypical carcinoid (AD) as intermediate-grade malignant tumors, and large cell NE carcinoma (LCNEC) and small cell lung carcinoma (SCLC), both of which are high-grade malignant tumors. This three-tiered classification is based solely on histologic grounds and is a source of controversy especially when dealing with borderline or “gray zone” categories (TC vs. AC, AC vs. LCNEC, LCNEC and SCLC). In this review, controversial issues regarding the histologic classification will be discussed, and an innovative grading system that incorporates Ki-67 labeling index will be described. In addition, the recently discovered molecular alterations involved in TC/AC, as well as pathways involved in high-grade NE carcinomas, will be discussed in order to elucidate the differences in pathogenesis and biology between carcinoid tumors and high-grade NE carcinomas. [ABSTRACT FROM AUTHOR]

Abstract: Background: Genetic alterations for targeting therapy are largely unexplored issues in pulmonary sarcomatoid carcinoma (PSC), a life-threatening tumor subset. Methods: EGFR, HER2, KRAS, p53, CTNNB1, BRAF and PIK3CA mutations were assessed by direct sequencing, ALK, EGFR and HER2 gene status by fluorescence in situ hybridization (FISH), and ALK protein expression by immunohistochemistry (IHC) in 20 pleomorphic carcinomas (PLC), two pulmonary blastomas (PB) and one carcinosarcoma (CS). Surgical specimens and, in case of positivity, the corresponding preoperative biopsies were analyzed. Furthermore, 51 consecutive metastatic lung adenocarcinomas (MELAD) were used as controls for FISH and IHC assays of ALK gene. Results: While no rearrangements of ALK were detected in PSC, relevant amplification was identified 5/23 (22%) surgical specimens and paired biopsies (four PLC and one PB, two females and three males, four current and one never smoker, aged 30–83 years). Considering tumor heterogeneity, the percentage of ALK amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain (GCG±SD) of 6.9±0.8 and no signal differences between the epithelial (6.5±0.9) and the sarcoma-like components (6.8±0.9) of tumors. In the remaining 18 non-amplified PSC, the relevant value was 2.9±0.5 in 1–80% tumor cells (p <0.001). ALK amplification was closely associated with chromosome 7 (EGFR) or 17 (HER2) polysomy (p <0.001). Out of 51 MELAD, 10 were ALK-rearranged (p =0.026) and only one amplified (p =0.009). No amplified tumors, either PSC or MELAD, expressed the relevant protein by IHC, while the 10 ALK-rearranged MELAD were strongly positive. TP53, KRAS and CTNNB1 mutations accounted for 30%, 22%, and 4% of cases, respectively, with no significant relationship with ALK amplification. No mutations for EGFR, HER2, BRAF or PIK3CA gene were observed. Conclusion: ALK gene amplification is a nonrandom and clonally related event in a subset of PSC, but its biologic rationale deserves further investigation. KRAS mutation could represent a novel tool for therapy of such so deadly tumors with MEK inhibitors. [Copyright &y& Elsevier]

Abstract: Background: The hypothesis that chemotherapy increases morbidity after pneumonectomy remains under debate, as the results of previous surgical series remain controversial. The hypothesis of the study is that patients who received preoperative chemotherapy may have subclinical parenchymal damage, increasing their risk of respiratory complications. Methods: The study population was composed of 10 patients who underwent pneumonectomy after chemotherapy for lung cancer (cisplatin+gemcitabine) randomly selected from our database and compared with 10 matched patients who underwent pneumonectomy without previous chemotherapy during the same period. Healthy lung tissue was obtained from surgical specimens, processed according to standard methods and evaluated on ematossilin and eosin-stained sections. Two pathologists without information on the preoperative treatment were asked to review the slides in order to reach a consensus on the type and extent of lung damage. Relevant information was then compared with functional tests and postoperative outcome. Results: Severe and diffuse (more than 50% of lung parenchyma) interstitial alterations were detected in the lungs of eight patients, seven of which belonged to the chemotherapy group (70%, p 0.02). Six of these patients developed postoperative respiratory complications. In the chemotherapy group, patterns of interstitial involvement were variable interstitial inflammation and fibrosis associated with obliterative bronchiolitis [Roberts JR, Eustis C, Devore R, et al. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung carcinoma. Ann Thorac Surg 2001;72:885–8], bronchiolitis obliterans-organizing pneumonia [Leo F, Solli P, Veronesi G, et al. Does chemotherapy increase the risk of respiratory complications after pneumonectomy? J Thorac Cardiovasc Surg 2006;132:519–23], diffuse alveolar damage [Novoa N, Varela G, Jimenez MF. Morbidity after surgery for non-small cell lung carcinoma is not related to neoadjuvant chemotherapy. Eur J Cardiothor Surg 2001;20:700–4], DIP (desquamative interstitial pneumonia)-like reaction [Roberts JR, Eustis C, Devore R, et al. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung carcinoma. Ann Thorac Surg 2001;72:885–8] and UIP (usual interstitial pneumonia)-like changes [Roberts JR, Eustis C, Devore R, et al. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung carcinoma. Ann Thorac Surg 2001;72:885–8]. The only preoperative clinical predictor of severe diffuse damage was preoperative diffusion by carbon monoxide (Dlco). Conclusions: Preoperative chemotherapy is associated with an increased risk of severe and diffuse pulmonary disease even in the presence of normal spirometric parameters. These alterations may play an important role in the occurrence of postoperative respiratory complications. [Copyright &y& Elsevier]

Background: Hamartomas constitute 8% of solitary lung nodules and 75% of benign nodules. Most are discovered on routine x-ray film and require further evaluation. Computed tomography (CT) is insufficient for a benign versus malignant diagnosis in about 30% of cases. Methods: We retrospectively assessed the ability of CT with contrast and [18F] fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) to diagnose nonmalignancy in 42 consecutive pathologically confirmed hamartomas, with the aim of reducing the number of invasive procedures in future cases. Computed tomography was assessed as probably benign or probably malignant based on one radiologist''s subjective evaluation. The PET/CT images were assessed according to uptake relative to normal parenchyma and mediastinum. Results: Computed tomography was probably benign in 26 cases (62%) and probably malignant in 16 (38%). The PET/CT scan was benign in 34 cases (81% [standard uptake value available in 16: mean 1.1, SD 0.5]), suspicious in 4 (9.5%), and malignant in 4 (9.5%). The 34 nodules benign by PET/CT had mean size 14.3 mm (SD 7.8) compared with mean 22.7 mm (SD 10) in the 8 nodules malignant/suspicious by PET/CT. Of these 8 nodules, 6 were probably benign by CT and 2 were probably malignant; thus CT and PET/CT concurred on malignancy in only 2 cases. Conclusions: The present study is the first specifically concerned with the CT and PET/CT characteristics of a pathologically confirmed series of lung hamartomas. Our findings support the role of PET/CT in characterizing solitary lung nodules, although about 20% of (mainly large size) hamartomas had uptake characteristics suggesting malignancy. [Copyright &y& Elsevier]

Summary: Detailed studies on the pathologic and molecular features of low-dose computed tomography (LDCT)-detected carcinomas and comparison with unscreened tumors are still lacking. We evaluated the histopathologic features of 89 LDCT-detected lung cancers resected between 2004 and 2006. These tumors occurred within a cohort of 5202 volunteers undergoing annual LDCT, aged ≥50 years, and with a minimum 20 pack-year index. In adenocarcinomas, central scar diameter, invasion foci size and K-ras mutations were also assessed. The results were compared with those of 89 consecutive lung carcinomas matched for confounding factors (sex, smoking habit), selected from group of 363 consecutive clinically worked-up lung cancer, surgically resected in the same period and at the same Institution. The tumors were diagnosed in 63 males and 26 females (range 50–79 years), 55 of which diagnosed at the baseline (1.05%) and 34 (including 10 repeat cancers) operated after work-up during the second year (0.72%). LDCT-detected tumors showed high resectability rate (89%), earlier stage (63%) and prevalence of adenocarcinoma nodules (72%), most often of the mixed subtype, in comparison with unscreened tumors. A similar prevalence of K-ras mutations was found in both screened and unscreened adenocarcinomas. Repeat cancers were found in 10 screened patients, and were predominantly stage I adenocarcinomas of mixed subtype exhibiting smaller dimension but greater central scar diameter and stromal invasion size in comparison with the other second-year, slower-growing adenocarcinomas. Multiple tumor nodules were identified in 10 patients exclusively at the baseline, were mostly mixed adenocarcinomas and differed in their K-ras mutation profile. Screening-detected lung cancers shared most of the histologic features of fully malignant tumors, in addition to a similar prevalence of K-ras mutations, despite their earlier detection and less advanced clinical stage. Repeat cancers are potentially aggressive tumors. K-ras mutation analysis supports the impression that multifocal tumors at baseline are separate synchronous primaries. [Copyright &y& Elsevier]

Objective: The main challenge of screening a healthy population with low-dose computed tomography is to balance the excessive use of diagnostic procedures with the risk of delayed cancer detection. We evaluated the pitfalls, difficulties, and sources of mistakes in the management of lung nodules detected in volunteers in the Cosmos single-center screening trial. Methods: A total of 5201 asymptomatic high-risk volunteers underwent screening with multidetector low-dose computed tomography. Nodules detected at baseline or new nodules at annual screening received repeat low-dose computed tomography at 1 year if less than 5 mm, repeat low-dose computed tomography 3 to 6 months later if between 5 and 8 mm, and fluorodeoxyglucose positron emission tomography if more than 8 mm. Growing nodules at the annual screening received low-dose computed tomography at 6 months and computed tomography-positron emission tomography or surgical biopsy according to doubling time, type, and size. Results: During the first year of screening, 106 patients underwent lung biopsy and 91 lung cancers were identified (70% were stage I). Diagnosis was delayed (false-negative) in 6 patients (stage IIB in 1 patient, stage IIIA in 3 patients, and stage IV in 2 patients), including 2 small cell cancers and 1 central lesion. Surgical biopsy revealed benign disease (false-positives) in 15 cases (14%). Positron emission tomography sensitivity was 88% for prevalent cancers and 70% for cancers diagnosed after first annual screening. No needle biopsy procedures were performed in this cohort of patients. Conclusion: Low-dose computed tomography screening is effective for the early detection of lung cancers, but nodule management remains a challenge. Computed tomography-positron emission tomography is useful at baseline, but its sensitivity decreases significantly the subsequent year. Multidisciplinary management and experience are crucial for minimizing misdiagnoses. [Copyright &y& Elsevier]

Abstract: Background: Digital nuclear morphometric analysis can capture subtle differences along neoplastic progression. Studies showed different profiles from normal to cancer lesions. Our goal is to utilize this method as biomarker in chemoprevention trials. Methods: Postmenopausal women were randomized to oral (CEE) or transdermal (E2) estrogen replacement therapy (ERT) in association with fenretinide or placebo. Ultrasound-guided fine needle aspiration (FNA) was performed at baseline and after 12 months in a subset of subjects. Results: Ten samples were analyzed by karyometry. E2 compared with CEE increased nuclear area (p=0.01). A similar pattern was observed for other DNA content and chromatin texture features. Fenretinide vs. placebo, increased nuclear area and shape while decreased slope, peak and entropy. Conclusion: Preliminary results indicate that nuclear morphometry is feasible on FNA samples. ERT and fenretinide induced significant karyometric changes. These results support further investigation of this procedure as surrogate biomarker in chemoprevention trial. [Copyright &y& Elsevier]

Background: Indeterminate noncalcified lung nodules are a frequent finding when low-dose computed tomography (LD-CT) is used for lung cancer screening. The best clinical management for such nodules remains uncertain. We present results using positron tomography scanning (CT-PET) to evaluate LD-CT–detected lung nodules during the first year of the Continuing Observation of Smoking Subjects (COSMOS) early detection trial for lung cancer. Methods: A total of 5200 asymptomatic current or former smokers (≥20 pack-years) older than 50 years of age were enrolled in a single-institution screening trial using annual LD-CT. Growing nodules and those with a maximum diameter exceeding 8 mm were studied with CT-PET. Transthoracic needle biopsy was not a routine part of the protocol. Results: During the first year of study, 157 subjects underwent CT-PET, 66 of whom underwent surgical biopsy. Of the 58 lung cancers found on surgical biopsy, 51 were positive (standard uptake value >2.0) and seven were negative for malignancy by CT-PET. Sensitivity was 88% overall, but 100% in the subgroup with solid nodules of 10 mm or more. Among the 8 patients with benign disease at surgical biopsy, CT-PET was positive in 6 and negative in 2. Conclusions: CT-PET is a highly promising modality for identifying potentially malignant lesions in screening-detected lung nodules and appears particularly useful as an alternative, in the screening setting, to invasive procedures for the further investigation of uncertain nodules. Our findings also indicate that the standard uptake value threshold for positivity should be lowered for small nodules (<10 mm). Longer follow-up and larger prospective studies are necessary to confirm these preliminary findings. [Copyright &y& Elsevier]

Summary: Between 1998 and 2003 we observed 15 women who underwent full thickness chest wall resection (FTCWR) followed by plastic reconstruction for locally recurrent or primary breast cancer. Preoperative symptoms were: pain (5 patients), malodorous ulceration (3 patients), presence of tumour mass (4 patients) and thoracic deformity (2 patients). One patient was asymptomatic. Surgery was partial sternectomy with rib resection in 9 patients, rib resection alone in 5, and total sternectomy in one. No perioperative mortality or major morbidity occurred; minor complications occurred in 3 patients (20%). Five of the six surviving patients reported a positive overall outcome in a telephonic interview. Median overall and disease-free survival were 23.4 and 17.5 months, respectively. In conclusion, FTCWR is a safe procedure with low morbidity and mortality that can provide good symptoms palliation in patients with locally advanced breast malignancies, so it should be considered more often by interdisciplinary care providers in those patients who fail to respond to classic multimodality treatment. [Copyright &y& Elsevier]

Objective: The impact of lymph node involvement in lung metastasectomy from extrapulmonary malignancies is uncertain. We assessed the prognostic value of lymph node status in lung metastasectomy and the prevalence of unexpected mediastinal lymph node involvement after lymph node sampling or dissection. Methods: From May 1998 to October 2005, 388 patients underwent 430 pulmonary metastasectomies with curative intent. The clinical records of all patients who underwent radical lymph node dissection or sampling were reviewed retrospectively. Survival was evaluated using the Kaplan–Meier method and comparison of survival curves by log–rank test. Results: A total of 124 patients (61 men, mean age 59 years) underwent 139 pulmonary metastasectomies (56 wedge resections, 30 segmentectomies, 49 lobectomies, and 4 pneumonectomies with radical lymph node dissection [88] or sampling [51]). Means of 9.4 lymph nodes and 2 lung metastases per intervention were removed. The median disease-free interval from primary treatment to lung metastasectomy was 49 months. Lymph node involvement was present in 25 patients (20%), in 10 (8%) at N1 stations (hilar or peribronchial) and in 15 (12%) at N2 stations (mediastinal), and in 7 (12.5%) after atypical resection and in 19 (23%) after typical resection. In 15 patients (12%) (60% of N+ patients), lymph node involvement was unexpected. Estimated overall 5-year survival was 46%: It was 60% for subjects with no lymph node metastasis and 17% and 0% for those with N1 and N2 disease, respectively (P = .01). Conclusions: Lymph node involvement heavily affects prognosis after pulmonary metastasectomies. In most patients, lymph node involvement was not revealed by preoperative workup. [Copyright &y& Elsevier]