Paolo Scanagatta

Lung cancer screening with low-dose computed tomography: A non-invasive diagnostic protocol for baseline lung nodules

BACKGROUND Indeterminate non-calcified lung nodules are frequent when low-dose spiral computed tomography (LD-CT) is used for lung cancer screening. We assessed the diagnostic utility of a non-invasive work-up protocol for nodules detected at baseline in volunteers enrolled in our single-centre screening trial, and followed for at least 1 year. METHODS 5201 high-risk volunteers, recruited over 1 year from October 2004, underwent baseline LD-CT; 4821 (93%) returned for the first repeat LD-CT. Nodules <or=5mm underwent repeat LD-CT at 1 year; nodules 5.1-8mm underwent LD-CT 3 months later; lesions >8mm received combined CT-positron emission tomography (CT-PET). A subset of nodules >8mm was studied by CT with contrast. Protocol failures were delayed diagnosis with disease progression beyond stage I, and negative surgical biopsy. RESULTS 2754 (53%) volunteers presented one or more non-calcified nodules. Ninety-two lung cancers were diagnosed: 55 at baseline and 37 at annual screening (66% stage I). Among the 37 incident cancers, 17 had a baseline nodule that remained stage I, 7 had a baseline nodule that progressed beyond stage I, and 13 presented a new malignant nodule. Baseline and annual cancers were 79 (1.5%) and 13 (0.2%), respectively. In 15 of 104 (14%) invasive diagnostic procedures, the lesion was benign. Sensitivity, and specificity were 91 and 99.7%, respectively, for the entire protocol; 88 and 93% for CT-PET; and 100 and 59% for CT with contrast. CONCLUSIONS The protocol limits invasive diagnostic procedures while few patients have diagnosis delay, supporting the feasibility of lung cancer screening in high-risk subjects by LD-CT. Nevertheless further optimization of the clinical management of screening-detected nodules is necessary.

ΔNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: A novel two-hit, sparing-material approach

Introduction: Diagnosing non-small cell lung cancer on biopsy/cellblock samples by morphology may be demanding. As sparing material for molecular testing is mandatory, a minimalist immunohistochemistry (IHC)-based diagnostic approach is warranted by means of novel, reliable, and easy-to-assess biomarkers. Methods: Forty-six consecutive biopsy/cellblock samples and the corresponding resection specimens (as the gold standard for morphology and IHC) from 30 adenocarcinomas (AD), 10 squamous carcinomas (SQC), 5 adenosquamous carcinomas (ADSQC), and 1 sarcomatoid carcinoma (SC) were IHC-evaluated for p40 [corresponding to nontransactivating &Dgr;Np63 isoforms] and thyroid transcription factor-1 (TTF1) by semiquantitative assessment. For p40, also immunodecoration intensity was taken into account and dichotomized as strong or low. Results: Nonrandom and overlapping distributions of the relevant markers were found in biopsy/cellblock and surgical specimens, which closely correlated with each other and the diverse tumor categories, with no differences in area under curve-receiver-operating-characteristic curves for each marker between any two samples, including p40 and p63. Diagnostic combinations were p40−/TTF1+ or TTF1− for AD (where p40 was negative, apart from 5/30 AD showing at the best 1–2% tumor cells with low intensity); p40+/TTF1− (p40 strong and by far higher than 50%) for SQC; and p40+/TTF1+ or p40+/TTF1− (p40 strong and less than 50%) for ADSQC. The single SC case was p40−/TTF1−, suggesting glandular lineage. Practically, 41/46 (89%) tumors were correctly classified by IHC on small samples, including 30 AD, 10 SQC, 1/5 ADSQC, and no SC. Underdiagnosis of ADSQC was actually because of sampling error of biopsies/cellblocks rather than insufficient biomarker robustness, whereas underdiagnosis of SC was really because of the failure of either marker to highlight epithelial-mesenchymal transition. Conclusions: This minimalist IHC-based model of p40 and TTF1 on biopsy/cellblock samples was effective to correctly subtype most cases of lung cancer.

Multiparametric molecular characterization of pulmonary sarcomatoid carcinoma reveals a nonrandom amplification of anaplastic lymphoma kinase (ALK) gene

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.

Difficulties encountered managing nodules detected during a computed tomography lung cancer screening program

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.

Surgery of non-small cell lung cancer in the elderly

Purpose of review The aim of this review is to analyze recent evidence for optimal treatment of elderly patients with non-small cell lung cancer, focusing on surgery, and possibly to foresee the future strategies to apply in these patients. Recent findings Surgery in elderly patients affected by non-small cell lung cancer is safe and feasible when careful preoperative respiratory and cardiac studies have been carried out and the disease has been properly staged. The surgical treatment is not to be denied in elderly patients due to age per se, but when a major contraindication to surgery has been recognized. Long term survival for elderly patients with early stage lung cancer treated by anatomical pulmonary resection is comparable to the survival rate of younger patients. Pneumonectomy, extended surgical procedure or preoperative induction chemotherapy are major risk factors for an increased postoperative morbidity and mortality rate. When co-morbidities are present or a patient is 80 years or older, there is evidence that a non-anatomical resection can be performed without affecting long-term results. Summary Due to the aging of the general population, elderly patients will become a large percentage of the cases of non-small cell lung cancer to be treated. Implementing preoperative cardiologic studies and redefining selective respiratory criteria specifically could dramatically improve results.

Adjuvant Surgery after Carboplatin and VP16 in Resectable Small Cell Lung Cancer

Introduction: The real benefit of surgical treatment of small cell lung cancer (SCLC) has never been demonstrated, mainly because of the rarity of surgical cases and the difficulty in comparing surgical and medical series for the different classifications systems used by surgeons (tumor, node, metastasis) and medical oncologists and radiotherapists (Veterans Administrations Lung Cancer Study Group). Materials and Methods: We prospectively assessed the utility of surgery after chemotherapy (carboplatin plus VP16 with or without ifosfamide) with or without radiotherapy in 23 patients with preoperative diagnosis of resectable stage I to IIIA SCLC. A median of three (range: three to six) courses of chemotherapy were administered. Five pneumonectomies, 12 lobectomies (seven sleeve resections), and two segmentectomies were performed, and all except one received radical lymph node dissection. Four (17%) patients received exploratory thoracotomy. Nine (39%) patients received postoperative thoracic radiotherapy. Results: Pathological stages were complete response in four patients, stage I in seven patients, stage II in seven patients, and stage III in five patients. Thirty-day morbidity and mortality were 9% and 0%, respectively. Surgery-related mortality at 90 days was 9%. Median follow-up was 19 months. Overall and local relapse rates were 52% and 17%, respectively. Median overall and disease-free survival were 24 and 12 months. Patients with complete response or pathological stage I had a significantly better Kaplan–Meier survival and lower incidence of relapse than those with more advanced pathological stage (p = 0.025 and 0.027, respectively, log rank). Conclusions: Survival after chemotherapy and surgery in the series correlated with pathological but not pretreatment stage. Only patients with pathological stage 0 or I disease seem to benefit from surgical resection.

Impaired quality of life after pneumonectomy: Who is at risk?

OBJECTIVE After pneumonectomy, quality of life may be impaired in a proportion of patients because of the presence of symptoms causing severe limitations in daily activities. This is a prospective study on patients who have undergone pneumonectomy for cancer, assessing quality of life modifications 6 months after surgery. METHODS Beginning in August 2006, candidates for pneumonectomy had their quality of life assessed by the European Organization for Research and Treatment of Cancer questionnaire (QLQ-C30 + LC13) preoperatively and at 1, 3, and 6 months after surgery. Poor quality of life at 6 months was defined as global health values 10% or more below baseline values. The impact of several clinical variables was tested to discover predictors of poor postoperative quality of life. RESULTS Forty-one of the 50 patients enrolled in the study had a complete quality of life follow-up by January 2008, representing the population of the study. Six months after pneumonectomy, global health showed a minimal impairment in the whole population (baseline 60.4 + or - 26.5, at 6 months 56.3 + or - 24.2, P = .15). Ten patients (24.4%) were identified as having poor quality of life at 6 months. Age of 70 years or more was identified as a significant risk factor for poor 6-month quality of life using multivariate analysis (odds ratio, 1.13; 95% confidence interval, 1-1.26). The baseline global health score was the strongest predictor of postoperative global health quality of life (odds ratio, 0.16; 95% confidence interval, 0.02-0.46; P = .0086). CONCLUSION The overall quality of life after pneumonectomy was impaired in 25% of surviving patients at 6 months after surgery; thus, this aspect of recovery should be routinely discussed with patients before pneumonectomy. Patients aged 70 years or more and those with low preoperative quality of life seem to be at risk for unsatisfactory quality of life after surgery.

Diagnosis and management of typical and atypical lung carcinoids.

An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1-5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids.

Paraneoplastic extra limbic encephalitis associated with thymoma.

We report the case of a 55-year-old woman with thymoma diagnosed after finding of extra limbic encephalitis. She presented neurologic symptoms as seizure and aphasia; magnetic resonance imaging (MRI) of the brain showed multiple lesions located in insular, parietal and temporal lobes (in cortical and sub-cortical area). Brain biopsies confirmed the diagnosis of encephalitis and CT-scan of the thorax showed an anterior mediastinal mass suspected for thymoma. The patient was submitted to thymectomy through a median sternotomy and we assisted to secondary reduction of cerebral lesions and total remission of symptoms.

Genomic characterization of asymptomatic CT-detected lung cancers

Computed tomography (CT) screening of lung cancer allows the detection of early tumors. The objective of our study was to verify whether initial asymptomatic lung cancers, identified by high-resolution low-dose CT (LD-CT) on a high-risk population, show genetic abnormalities that could be indicative of the early events of lung carcinogenesis. We analyzed 78 tumor samples: 21 (pilot population) from heavy smokers with asymptomatic non-screening detected early-stage lung cancers and 57 from 5203 asymptomatic heavy smoker volunteers, who underwent a LD-CT screening study. During surgical resection of the detected tumors, tissue samples were collected and short-term cultures were started for karyotype evaluation. Samples were classified according to the normal (NK) or aneuploid (AK) karyotype. The NK samples were further analyzed by the Affymetrix single-nucleotide polymorphisms (SNPs) technology. Metaphase spreads were obtained in 73.0% of the selected samples: 80.7% showed an AK. A statistically significant correlation was found between presence of vascular invasion and abnormal karyotype. A total of 10 NK samples were suitable for SNPs analysis. Subtle genomic alterations were found in eight tumors, the remaining two showing no evidence to date of chromosomal aberrations anywhere in the genome. Two common regions of amplification were identified at 5p and 8p11. Mutation analysis by direct sequencing was conducted for the K-RAS, TP53 and EGFR genes, confirming data already described for heavy smokers. We show that: (i) the majority of screening-detected tumors are aneuploid; (ii) early-stage tumors tend to harbor a less abnormal karyotype; (iii) whole genome analysis of NK tumors allows for the detection of common regions of copy number variation (such as amplifications at 5p and 8p11), highlighting genes that might be considered candidate markers of early events in lung carcinogenesis.