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1.  Asymptomatic colonic metastases from primary squamous cell carcinoma of the lung with a positive fecal occult blood test 
We describe a 74-year-old man with a colonic metastatic squamous cell carcinoma (SCC) from the lung. His chest X-ray revealed an abnormal shadow in the right upper lobe. Computed tomography (CT) of the chest demonstrated a large lung tumor in the right upper lobe obstructing the right upper bronchus. Bronchoscopy revealed an easy-bleeding tumor in the right upper bronchus that was diagnosed as poorly differentiated squamous cell lung carcinoma. He underwent colonoscopy because he had a positive fecal occult blood test. Colonoscopy revealed a large protruding lesion with central ulceration in the descending colon. Histological examination of the biopsy specimen obtained from the colonic lesion revealed SCC. The lesion was diagnosed as metastatic colonic SCC. He had no abdominal symptoms. He underwent chemotherapy with an infusion of cisplatin 130 mg i.v. day 1, and docetaxel hydrate 100 mg i.v. day 1, repeated every 4 wk, followed by 4 courses of chemotherapy. The primary lesion shrank by less than 10% and was judged to be “Partial Response” (PR) after 3 courses of treatment. The patient still lived 23 wk after the diagnosis of metastatic colonic SCC. Colonic metastasis of primary SCC of the lung is rare.
doi:10.3748/wjg.14.5481
PMCID: PMC2744902  PMID: 18803365
Gastrointestinal metastatic tumor; Colonic metastasis; Large intestine; Colonoscopy; Chemotherapy
2.  Autofluorescence bronchoscopy for lung cancer surveillance based on risk assessment 
Thorax  2006;62(4):335-340.
Background
This is a preliminary report of an ongoing prospective bimodality lung cancer surveillance trial for high‐risk patients. Bimodality surveillance incorporates autofluorescence bronchoscopy (AFB) and spiral CT (SCT) scanning in high‐risk patients as a primary lung cancer surveillance strategy, based entirely on risk factors. AFB was used for surveillance and findings were compared with conventional sputum cytology for the detection of malignancy and pre‐malignant central airway lesions.
Methods
402 patients registering at Roswell Park Cancer Institute were evaluated with spirometric testing, chest radiography, history and physical examination, of which 207 were deemed eligible for the study. For eligibility, patients were required to have at least two of the following risk factors: (1) ⩾20 pack year history of tobacco use, (2) asbestos‐related lung disease on the chest radiograph, (3) chronic obstructive pulmonary disease with a forced expiratory volume in 1 s (FEV1) <70% of predicted, and (4) prior aerodigestive cancer treated with curative intent, with no evidence of disease for >2 years. All eligible patients underwent AFB, a low‐dose SCT scan of the chest without contrast, and a sputum sample was collected for cytological examination. Bronchoscopic biopsy findings were correlated with sputum cytology results, SCT‐detected pulmonary nodules and surveillance‐detected cancers. To date, 186 have been enrolled with 169 completing the surveillance procedures.
Results
Thirteen lung cancers (7%) were detected in the 169 subjects who have completed all three surveillance studies to date. Pre‐malignant changes were common and 66% of patients had squamous metaplasia or worse. Conventional sputum cytology missed 100% of the dysplasias and 68% of the metaplasias detected by AFB, and failed to detect any cases of carcinoma or carcinoma‐in‐situ in this patient cohort. Sputum cytology exhibited 33% sensitivity and 64% specificity for the presence of metaplasia. Seven of 13 lung cancers (58%) were stage Ia or less, including three patients with squamous cell carcinoma. Patients with peripheral pulmonary nodules identified by SCT scanning of the chest were 3.16 times more likely to exhibit pre‐malignant changes on AFB (p<0.001).
Conclusion
Bimodality surveillance will detect central lung cancer and pre‐malignancy in patients with multiple lung cancer risk factors, even when conventional sputum cytology is negative. AFB should be considered in high‐risk patients, regardless of sputum cytology findings.
doi:10.1136/thx.2006.068999
PMCID: PMC2092474  PMID: 17101735
3.  Synchronous double primary lung cancers via p53 pathway induced by heavy smoking 
Annals of Saudi Medicine  2010;30(3):236-238.
Differences in the histological manifestation of synchronous lung cancers are rare. Synchronous multiple primary lung cancers (SMPLC) are associated with long-term tobacco use, which could independently lead to mutations in the p53 and K-ras genes. We present the case of an 82-year-old man who smoked 30 cigarettes daily for the past 60 years. CT of the chest showed a right upper lobe mass. Bronchoscopy revealed an intra-lumen nodular lesion in the right lower lobe bronchus. The diagnoses of small cell lung carcinoma (SCLC) of the right upper lobe and non-small cell lung carcinoma (NSCLC) of the right lower lobe were confirmed by the morphologic features and the detected immunoreactivity. Immunohistochemical analyses showed a strong positive reaction for p53 in samples of the SCLC and NSCLC. The cancers had a different phenotype, but similar genetic abnormalities may have developed due to the carcinogens in the cigarettes.
doi:10.4103/0256-4947.62837
PMCID: PMC2886876  PMID: 20427942
4.  Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer 
PLoS Medicine  2010;7(12):e1000378.
David Mangelsdorf and colleagues show that nuclear receptor expression is strongly associated with clinical outcomes of lung cancer patients, and this expression profile is a potential prognostic signature for lung cancer patient survival time, particularly for individuals with early stage disease.
Background
The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer.
Methods and Findings
Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis.
Conclusions
NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer, the most common cause of cancer-related death, kills 1.3 million people annually. Most lung cancers are “non-small-cell lung cancers” (NSCLCs), and most are caused by smoking. Exposure to chemicals in smoke causes changes in the genes of the cells lining the lungs that allow the cells to grow uncontrollably and to move around the body. How NSCLC is treated and responds to treatment depends on its “stage.” Stage I tumors, which are small and confined to the lung, are removed surgically, although chemotherapy is also sometimes given. Stage II tumors have spread to nearby lymph nodes and are treated with surgery and chemotherapy, as are some stage III tumors. However, because cancer cells in stage III tumors can be present throughout the chest, surgery is not always possible. For such cases, and for stage IV NSCLC, where the tumor has spread around the body, patients are treated with chemotherapy alone. About 70% of patients with stage I and II NSCLC but only 2% of patients with stage IV NSCLC survive for five years after diagnosis; more than 50% of patients have stage IV NSCLC at diagnosis.
Why Was This Study Done?
Patient responses to treatment vary considerably. Oncologists (doctors who treat cancer) would like to know which patients have a good prognosis (are likely to do well) to help them individualize their treatment. Consequently, the search is on for “prognostic tumor biomarkers,” molecules made by cancer cells that can be used to predict likely clinical outcomes. Such biomarkers, which may also be potential therapeutic targets, can be identified by analyzing the overall pattern of gene expression in a panel of tumors using a technique called microarray analysis and looking for associations between the expression of sets of genes and clinical outcomes. In this study, the researchers take a more directed approach to identifying prognostic biomarkers by investigating the association between the expression of the genes encoding nuclear receptors (NRs) and clinical outcome in patients with lung cancer. The NR superfamily contains 48 transcription factors (proteins that control the expression of other genes) that respond to several hormones and to diet-derived fats. NRs control many biological processes and are targets for several successful drugs, including some used to treat cancer.
What Did the Researchers Do and Find?
The researchers analyzed the expression of NR mRNAs using “quantitative real-time PCR” in 30 microdissected NSCLCs and in matched normal lung tissue samples (mRNA is the blueprint for protein production). They then used an approach called standard classification and regression tree analysis to build a prognostic model for NSCLC based on the expression data. This model predicted both survival time and disease recurrence among the patients from whom the tumors had been taken. The researchers validated their prognostic model in two large independent lung adenocarcinoma microarray datasets and in a squamous cell carcinoma dataset (adenocarcinomas and squamous cell carcinomas are two major NSCLC subtypes). Finally, they explored the roles of specific NRs in the prediction model. This analysis revealed that the ability of the NR signature in tumors to predict outcomes was mainly due to the expression of two NRs—the short heterodimer partner (SHP) and the progesterone receptor (PR). Expression of either gene could be used as a single gene predictor of the survival time of patients, including those with stage I disease. Similarly, the expression of either nerve growth factor induced gene B3 (NGFIB3) or mineralocorticoid receptor (MR) in normal tissue was a single gene predictor of a good prognosis.
What Do These Findings Mean?
These findings indicate that the expression of NR mRNA is strongly associated with clinical outcomes in patients with NSCLC. Furthermore, they identify a prognostic NR expression signature that provides information on the survival time of patients, including those with early stage disease. The signature needs to be confirmed in more patients before it can be used clinically, and researchers would like to establish whether changes in mRNA expression are reflected in changes in protein expression if NRs are to be targeted therapeutically. Nevertheless, these findings highlight the potential use of NRs as prognostic tumor biomarkers. Furthermore, they identify SHP and PR in tumors and two NRs in normal lung tissue as molecules that might provide new targets for the treatment of lung cancer and new insights into the early diagnosis, pathogenesis, and chemoprevention of lung cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000378.
The Nuclear Receptor Signaling Atlas (NURSA) is consortium of scientists sponsored by the US National Institutes of Health that provides scientific reagents, datasets, and educational material on nuclear receptors and their co-regulators to the scientific community through a Web-based portal
The Cancer Prevention and Research Institute of Texas (CPRIT) provides information and resources to anyone interested in the prevention and treatment of lung and other cancers
The US National Cancer Institute provides detailed information for patients and professionals about all aspects of lung cancer, including information on non-small-cell carcinoma and on tumor markers (in English and Spanish)
Cancer Research UK also provides information about lung cancer and information on how cancer starts
MedlinePlus has links to other resources about lung cancer (in English and Spanish)
Wikipedia has a page on nuclear receptors (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000378
PMCID: PMC3001894  PMID: 21179495
5.  Autofluorescence bronchoscopy with white light bronchoscopy compared with white light bronchoscopy alone for the detection of precancerous lesions: a European randomised controlled multicentre trial 
Thorax  2005;60(6):496-503.
Background: The potential of autofluorescence bronchoscopy (AFB) to detect precancerous lesions in the central airways and its role in lung cancer screening is uncertain. A study was undertaken to evaluate the prevalence of moderate/severe dysplasia (dysplasia II–III) and carcinoma in situ (CIS) using a newly developed AFB system in comparison with conventional white light bronchoscopy (WLB) alone.
Methods: In a prospective randomised multicentre trial, smokers ⩾40 years of age (⩾20 pack-years) were stratified into four different risk groups and investigated with either WLB+AFB (arm A) or WLB alone (arm B).
Results: 1173 patients (916 men) of mean age 58.7 years were included. Overall (arms A and B), preinvasive lesions (dysplasia II–III and CIS) were detected in 3.9% of the patients. The prevalence of patients with preinvasive lesions in the WLB arm was 2.7% compared with 5.1% in the WLB+AFB arm (p = 0.037). For patients with dysplasia II–III, WLB+AFB increased the detection rate by a factor of 2.1 (p = 0.03), while for CIS the factor was only 1.24 (p = 0.75). The biopsy based sensitivity of WLB alone and WLB+AFB for detecting dysplasia II–III and CIS was 57.9% compared with 82.3% (1.42-fold increase). The corresponding specificity was 62.1% compared with 58.4% (0.94-fold decrease).
Conclusions: This first randomised study of AFB showed that the combination of WLB+AFB was significantly superior to WLB alone in detecting preneoplastic lesions. Our findings do not support the general use of AFB as a screening tool for lung cancer, but suggest that it may be of use in certain groups. The precise indications await further study.
doi:10.1136/thx.2005.041475
PMCID: PMC1747416  PMID: 15923251
6.  Rare coexistence of sarcoidosis and lung adenocarcinoma 
Case
An eighty year old African-American female was evaluated for cough, chest pain, asymptomatic anemia and 21 pound weight loss over a six month period. Computerized tomography (CT) revealed a spiculated 2.8 cm right upper lobe lung nodule, other smaller nodules and lymphadenopathy. Gallium scan revealed abnormal uptake of radiotracer in lacrimal, hilar and mediastinal glands. Broncho-alveolar lavage showed CD4/CD8 ratio of 2:1 with 15% lymphocytes. Biopsy of right upper lobe lesion and mediastinoscopic lymph node biopsy showed numerous matured uniform non-caseating granulomatous inflammation, however stains and culture for Acid fast bacilli (AFB)/fungal organisms were negative. Patient improved on oral steroids. Six months later she returned with worsening dyspnea and chest X-ray showed bilateral pleural effusions. Thoracocentesis revealed Thyroid transcription factor 1 (TTF1) positive adenocarcinoma cells and Video assisted thoracic surgery (VATS) procedure revealed numerous pleural, pericardial, diaphragmatic metastasis. Biopsy also was positive for TTF1 adenocarcinoma and positive for Epidermal Growth Factor receptor (EGFR) mutation, however negative for Anaplastic Lymphoma Kinase (ALK). Talc pleurodesis was performed. She was treated with erlotinib while steroid was kept on hold. Initial tumor burden decreased but follow-up PET scan six months later showed progression of tumor with lymphadenopathy. After discussion with patient and family, patient opted for hospice care.
Discussion
Oncocentric theory postulates sarcoidosis as an immunological reaction to dispersal of tumor antigen. Sarcocentric theory postulates that cell-mediated immune abnormalities induced by sarcoidosis in CD4 and CD8 cells is involved in the onset of lung cancer. Thus considerable controversy exists regarding sarcoidosis and malignancy. In our case, TTF1 adenocarcinoma cells from thoracocentesis suggest peripheral nodules in right upper lobe and lingula were likely metastatic, presenting as malignant pleural effusions. However if noncaseating granulomatous inflammation is expected as an immunological reaction to tumor antigen, it is very interesting to observe that initial tissue biopsy of primary right upper lobe mass and mediastinal lymph nodes showed matured uniform non-caseating granulomatous inflammation and no evidence of adenocarcinoma. This being said, it would be highly unlikely for sarcoidosis to progress to lung adenocarcinoma within six months. This adds further controversy to whether granulomatous inflammation is a precursor to future malignancy or whether this elderly African-American female was predisposed to develop granulomatous inflammation in presence of a tumor antigen. One can also speculate whether repeat tissue sampling from right upper lobe mass would have shown granulomatous inflammation or TTF1 adenocarcinoma.
Conclusion
While evidence is still lacking regarding association between sarcoidosis and lung adenocarcinoma, it is important for clinicians to exclude metastatic malignancy in patients exhibiting clinical and radiographic findings consistent with sarcoidosis.
doi:10.1016/j.rmcr.2013.12.008
PMCID: PMC4061445
Sarcoidosis; Lung adenocarcinoma; Non-caseating granulomas; TTF-1 mutation; Tumor
7.  Complete video-assisted thoracoscopic surgery upper left bronchial sleeve lobectomy 
Journal of Thoracic Disease  2013;5(Suppl 3):S298-S300.
This video demonstrates a case undergoing complete video-assisted thoracoscopic surgery (VATS) upper left bronchial sleeve lobectomy. The 18-year-old female patient was admitted for recurrent cough and intermittent hemoptysis for one month. Chest CT scan showed a neoplasm in the left main bronchus and the left upper lobe bronchus. Bronchoscopic biopsy indicated mucinous epithelial cancer. Based on the chest CT findings, the left lower lung was not affected. To preserve normal lung tissue and minimize the loss of lung function, we decided to perform this surgical procedure. A three-port technique was conducted, in which the hypoplastic oblique fissure, the left upper pulmonary vein, and the upper lobe branch of the left pulmonary artery were initially treated under complete VATS. Bronchial sleeve lobectomy of the upper lobe of the left lung was finally carried out. The key to success was the end-to-end anastomosis between the left main bronchus and the lower left bronchus under thoracoscope. The deep location of the operative field partly hidden under the left pulmonary artery trunk during bronchial anastomosis made it even more difficult to operate thoracoscopically. To improve exposure of the operative field, we managed to raise the left main bronchus by passing two 1-0 silk sutures, respectively ligated with both sides of the posterior wall of the left main bronchus, through the anterior and posterior chest walls using a crochet needle. Similarly, a 1-0 silk suture was advanced through the posterior chest wall with a crochet needle to lift the trunk of the left pulmonary artery. In this way, a widely open, exposed field was achieved. Postoperative recovery was smooth. Chest X-ray showed good expansion of the left lung. Bronchoscopy indicated a patent anastomosis. The patient was discharged after two weeks. In conclusion, complete VATS bronchial sleeve lobectomy is a minimally invasive approach for thorough removal of tumor lesions while sparing as most normal lung tissue as possible, which avoids pneumonectomy and satisfies the psychological and physiological needs of patients.
doi:10.3978/j.issn.2072-1439.2013.08.29
PMCID: PMC3771595  PMID: 24040547
Video-assisted thoracoscopic surgery (VATS); sleeve lobectomy; lung cancer
8.  Fatal stroke after completion pneumonectomy for torsion of left upper lobe following left lower lobectomy 
Background
The lobar torsion after lung surgery is a rare complication with an incidence of 0.09 to 0.4 %. It may occur after twisting of the bronchovascular pedicle of the remaining lobe after lobectomy, usually on the right side. The 180-degree rotation of the pedicle produces an acute obstruction of the lobar bronchus (atelectasis) and of the lobar vessels as well. Without prompt treatment it progresses to lobar ischemia, pulmonary infarction and finally fatal gangrene.
Case Presentation
A 62 years old female patient was admitted for surgical treatment of lung cancer. She underwent elective left lower lobectomy for squamous cell carcinoma (pT2 N0). The operation was unremarkable, and the patient was extubated in the operating room. After eight hours the patient established decrease of pO2 and chest x-ray showed atelectasis of the lower lobe. To establish diagnosis, bronchoscopy was performed, demonstrating obstructed left lobar bronchus. The patient was re-intubated, and admitted to the operating room where reopening of the thoracotomy was performed. Lobar torsion was diagnosed, with the diaphragmatic surface of the upper lobe facing in an anterosuperior orientation. A completion pneumonectomy was performed. At the end of the procedure the patient developed a right pupil dilatation, presumably due to a cerebral embolism. A subsequent brain angio-CT scan established the diagnosis. She died at the intensive care unit 26 days later.
Conclusion
The thoracic surgeon should suspect this rare early postoperative complication after any thoracic operation in every patient with atelectasis of the neighboring lobe. High index of suspicion and prompt diagnosis may prevent catastrophic consequences, such as, infarction or gangrene of the pulmonary lobe. During thoracic operations, especially whenever the lung or lobe hilum is full mobilized, fixation of the remaining lobe may prevent this life threatening complication.
doi:10.1186/1749-8090-1-25
PMCID: PMC1584227  PMID: 16968544
9.  Detection of Pre-invasive Endobronchial Tumors with D-light/Autofluorescence System 
Journal of Korean Medical Science  2006;21(2):242-246.
Autofluorescence bronchoscopy (AFB) is one of the newly developed diagnostic tools to detect the pre-cancerous lesions in the bronchial tissue. The utility of D-Light/AFB in the detection of pre-cancerous lesions was compared to the standard white light bronchoscopy (WLB). In 113 patients (male 106, female 7), who visited hospital for evaluation of lung cancer, WLB and AFB were done and 364 biopsy specimens were obtained from November 2001 to August 2002. The bronchoscopic findings on WLB and AFB were compared to the pathological findings. The pathologic diagnoses of the specimens were as follows: normal in 96; hyperplasia in 69; metaplasia in 32; mild dysplasia in 13, moderate dysplasia in 6, severe dysplasia in 4; carcinoma in situ in 6; invasive carcinoma in 57. The relative sensitivity of adjunctive AFB to WLB vs. WLB alone was 1.5 in moderate dysplasia or worse lesions, and 3.2 in intraepithelial neoplasia. The specificity of adjunctive AFB and WLB alone were 0.91 and 0.5, respectively. The adjunctive AFB to the standard WLB increased the detection rate of the localized pre-invasive lesions. However, there was high rate of false positive in AFB.
doi:10.3346/jkms.2006.21.2.242
PMCID: PMC2733998  PMID: 16614508
Bronchoscopes, Fluorescence; Bronchoscopy; Lung Neoplasms
10.  Coexisting Bronchogenic Carcinoma and Pulmonary Tuberculosis in the Same Lobe: Radiologic Findings and Clinical Significance 
Korean Journal of Radiology  2001;2(3):138-144.
Objective
Bronchogenic Carcinoma Can Mimic Or Be Masked By Pulmonary Tuberculosis (Tb), And The Aim Of This Study Was To Describe The Radiologic Findings And Clinical Significance Of Bronchogenic Carcinoma And Pulmonary Tb Which Coexist In The Same Lobe.
Materials and Methods
The findings of 51 patients (48 males and three females, aged 48-79 years) in whom pulmonary TB and bronchogenic carcinoma coexisted in the same lobe were analyzed. The morphologic characteristics of a tumor, such as its diameter and margin, the presence of calcification or cavitation, and mediastinal lymphadenopathy, as seen at CT, were retrospectively assessed, and the clinical stage of the lung cancer was also determined. Using the serial chest radiographs available for 21 patients, the possible causes of delay in the diagnosis of lung cancer were analyzed.
Results
Lung cancers with coexisting pulmonary TB were located predominantly in the upper lobes (82.4%). The mean diameter of the mass was 5.3 cm, and most tumors (n=42, 82.4%) had a lobulated border. Calcification within the tumor was seen in 20 patients (39.2%), and cavitation in five (9.8%). Forty-two (82.4%) had mediastinal lymphadenopathy, and more than half the tumors (60.8%) were at an advanced stage [IIIB (n=11) or IV (n=20)]. The average delay in diagnosing lung cancer was 11.7 (range, 1-24) months, and the causes of this were failure to observe new nodules masked by coexisting stable TB lesions (n=8), misinterpretation of new lesions as aggravation of TB (n=5), misinterpretation of lung cancer as tuberculoma at initial radiography (n=4), masking of the nodule by an active TB lesion (n=3), and subtleness of the lesion (n=1).
Conclusion
Most cancers concurrent with TB are large, lobulated masses with mediastinal lymphadenopathy, indicating that the morphologic characteristics of lung cancer with coexisting pulmonary TB are similar to those of lung cancer without TB. The diagnosis of lung cancer is delayed mainly because of masking by a tuberculous lesion, and this suggests that in patients in whom a predominant or growing nodule is present and who show little improvement of symptoms despite antituberculous or other medical therapy, coexisting cancer should be suspected.
doi:10.3348/kjr.2001.2.3.138
PMCID: PMC2718111  PMID: 11752984
Lung neoplasms; Lung neoplasms, CT; Tuberculosis, pulmonary
11.  Lesions in patients with multifocal adenocarcinoma are more frequently in the right upper lobes 
OBJECTIVES
Opportunities to treat multifocal lung cancers, mostly adenocarcinoma, are increasing due to the development of imaging technologies. The optimal therapy modality to treat multifocally growing lung cancers remains obscure. To determine the features of multifocal lung cancers, we retrospectively reviewed patients with multiple lung lesions.
METHODS
Clinical, pathological and genetic characteristics of 31 patients with multifocal lesions were compared with those of patients who had had radical lung resection for solitary lung cancer. Gene mutation analyses for EGFR, KRAS and P53 were performed on three tumours of each of the patients who had four or more lesions.
RESULTS
Of the 31 patients, 17 had double tumours, 4 had triple tumours and 10 had 4 or more lesions. Patients with four or more lesions were significantly more likely to be females and never smokers. All of the histologically confirmed tumours of the cases with four or more lesions were adenocarcinoma in situ or lepidic predominant adenocarcinoma. The number of lesions in the right upper lobes when compared with the right lower lobes was significantly higher in patients with four or more lesions than in patients with double or triple lesions (P = 0.013). Five of the 12 tumours were positive for the EGFR mutation L858R in exon 21. No KRAS mutation was found.
CONCLUSIONS
Lesions in patients with multifocal adenocarcinoma are more frequently in the right upper lobes. Genetic analysis suggested that the specific EGFR mutation L858R in exon 21 might be the main factor contributing to lung carcinogenesis in multiple lung cancers. Further investigation of the right upper lobe in those patients compared with the lower lobes might provide more insights into lung carcinogenesis.
doi:10.1093/icvts/ivs276
PMCID: PMC3445368  PMID: 22733594
Lung cancer; Adenocarcinoma; Multiple lung tumour; EGFR mutation
12.  Integrative Genomic Analyses Identify BRF2 as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma 
PLoS Medicine  2010;7(7):e1000315.
William Lockwood and colleagues show that the focal amplification of a gene, BRF2, on Chromosome 8p12 plays a key role in squamous cell carcinoma of the lung.
Background
Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes—adenocarcinoma (AC) and squamous cell carcinoma (SqCC)—respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.
Methods and Findings
We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.
Conclusions
This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the commonest cause of cancer-related death. Every year, 1.3 million people die from this disease, which is mainly caused by smoking. Most cases of lung cancer are “non-small cell lung cancers” (NSCLCs). Like all cancers, NSCLC starts when cells begin to divide uncontrollably and to move round the body (metastasize) because of changes (mutations) in their genes. These mutations are often in “oncogenes,” genes that, when activated, encourage cell division. Oncogenes can be activated by mutations that alter the properties of the proteins they encode or by mutations that increase the amount of protein made from them, such as gene amplification (an increase in the number of copies of a gene). If NSCLC is diagnosed before it has spread from the lungs (stage I disease), it can be surgically removed and many patients with stage I NSCLC survive for more than 5 years after their diagnosis. Unfortunately, in more than half of patients, NSCLC has metastasized before it is diagnosed. This stage IV NSCLC can be treated with chemotherapy (toxic chemicals that kill fast-growing cancer cells) but only 2% of patients with stage IV lung cancer are alive 5 years after diagnosis.
Why Was This Study Done?
Traditionally, NSCLC has been regarded as a single disease in terms of treatment. However, emerging evidence suggests that the two major subtypes of NSCLC—adenocarcinoma and squamous cell carcinoma (SqCC)—respond differently to chemotherapy. Adenocarcinoma and SqCC start in different types of lung cell and experts think that for each cell type in the body, specific combinations of mutations interact with the cell type's own unique characteristics to provide the growth and survival advantage needed for cancer development. If this is true, then identifying the molecular differences between adenocarcinoma and SqCC could provide targets for more effective therapies for these major subtypes of NSCLC. Amplification of a chromosome region called 8p12 is very common in NSCLC, which suggests that an oncogene that drives lung cancer development is present in this chromosome region. In this study, the researchers investigate this possibility by looking for an amplified gene in the 8p12 chromosome region that makes increased amounts of protein in lung SqCC but not in lung adenocarcinoma.
What Did the Researchers Do and Find?
The researchers used a technique called comparative genomic hybridization to show that focal regions of Chromosome 8p are amplified in about 40% of lung SqCCs, but that DNA loss in this region is the most common alteration in lung adenocarcinomas. Ten genes in the 8p12 chromosome region were expressed at higher levels in the SqCC samples that they examined than in adenocarcinoma samples, they report, and overexpression of five of these genes correlated with amplification of the 8p12 region in the SqCC samples. Only one of the genes—BRF2—was more highly expressed in squamous carcinoma cells than in normal bronchial epithelial cells (the cell type that lines the tubes that take air into the lungs and from which SqCC develops). Artificially induced expression of BRF2 in bronchial epithelial cells made these normal cells behave like tumor cells, whereas reduction of BRF2 expression in squamous carcinoma cells made them behave more like normal bronchial epithelial cells. Finally, BRF2 was frequently activated in two early stages of squamous cell carcinoma—bronchial carcinoma in situ and dysplastic lesions.
What Do These Findings Mean?
Together, these findings show that the focal amplification of chromosome region 8p12 plays a role in the development of lung SqCC but not in the development of lung adenocarcinoma, the other major subtype of NSCLC. These findings identify BRF2 (which encodes a RNA polymerase III transcription initiation factor, a protein that is required for the synthesis of RNA molecules that help to control cell growth) as a lung SqCC-specific oncogene and uncover a unique mechanism for lung SqCC development. Most importantly, these findings suggest that genetic activation of BRF2 could be used as a marker for lung SqCC, which might facilitate the early detection of this type of NSCLC and that BRF2 might provide a new target for therapy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000315.
The US National Cancer Institute provides detailed information for patients and professionals about all aspects of lung cancer, including information on non-small cell carcinoma (in English and Spanish)
Cancer Research UK also provides information about lung cancer and information on how cancer starts
MedlinePlus has links to other resources about lung cancer (in English and Spanish)
doi:10.1371/journal.pmed.1000315
PMCID: PMC2910599  PMID: 20668658
13.  AB 29. Malignant mediastinal tumor: restrictions in immunohistochemical evaluation 
Journal of Thoracic Disease  2012;4(Suppl 1):AB29.
Background
It is common ground that immunohistochemistry’s contribution in neoplasm’s origin identification is invaluable. However, in some cases there seem to exist certain limitations raising differential diagnosis problems.
Patients and methods
A young 23-year old woman, who was recently pregnant and breastfeeding, presented to our hospital with dyspnea and superior vena cava syndrome. A month ago she suffered from upper respiratory tract infection, which was treated with antibiotics. Axial computed tomography showed several mediastinal masses and right lower lobe lung invasion. This was followed by bronchoscopy and samples were taken for biopsy.
Results
Upon histological evaluation a malignant neoplasm with extensive necrosis was revealed. Diffuse distribution of oval, middle to large size cells, with conspicuous nucleoli and mitoses, tend to lead to the diagnosis of a lymphoproliferative neoplasm. During to gradual and extensive immunohistochemical examination, the neoplastic cells were found negative to stains specific for hemopoietic system diseases as well as other malignant neoplasm such as sarcoma, mesothelioma, germ cell tumor, melanoma and neuroendocrine carcinoma. On the other hand, they were strongly positive for p63 (squamous cell differentiation index), CD138 and only weak and focally for keratins (CKAE1/AE3, CK8/18, CK7, CK5/6). Morphological and immunohistochemical findings consisted with undifferentiated carcinoma, with squamous cell differentiation. The patient deceased 20 days later.
Conclusions
Neoplastic morphological features tend to lead to a correct diagnosis which should always be certified by immunohistochemical findings. However, in some cases immunohistochemistry’s role is diminished due to tumor specific factors as neoplastic cells’ poor differentiation or dedifferentiation and degenerative changes.
doi:10.3978/j.issn.2072-1439.2012.s029
PMCID: PMC3537357
14.  Cytogenetic findings in lung cancer that illuminate its biological history from adenomatous hyperplasia to bronchioalveolar carcinoma to adenocarcinoma: A case report 
The biological and chronological evolution of lung cancer remain to be fully elucidated. A multi-step carcinogenesis hypothesis suggests a progression from atypical adenomatous hyperplasia (AAH) through bronchioalveolar carcinoma (BAC) to invasive adenocarcinoma (AC), but to date this has not been formally demonstrated. We report a case of a patient diagnosed by computed tomography (CT) with lung cancer in the superior right lobe who also presented with a pure ground-glass opacity (GGO) in the inferior lobe, while the middle lobe appeared normal. Following pneumonectomy, cytogenetic analysis successfully performed on spontaneous metaphases obtained by the direct method from samples of the three lung lobes showed the presence of three clonal cell populations, each progressively having increased karyotype complexity. Fluorescence in situ hybridization (FISH), performed using ALK (2p23) break probe and ALK/EML4 t(2;2);inv(2) fusion probe, showed a normal pattern for all specimens. Histological evaluation confirmed the presence of AC in the superior right lobe and classified the GGO lesion as BAC and the normal tissue of the middle lobe as AAH. To the best of our knowledge, this is the first case in which the cytogenetic study of spontaneous metaphases showed a clear clonal relationship among AC, BAC and AAH present simultaneously in different lobes of the same lung. This case appears to indicate that the entire lung was somehow predisposed to a neoplastic transformation starting with a diffuse AAH characterized by high proliferative activity. Moreover, the 5q13 region involved in the translocation shared by BAC and AC contains at least 4 genes encoding important regulators of the cell cycle that may be considered new molecular markers of lung cancer.
doi:10.3892/etm.2012.725
PMCID: PMC3494121  PMID: 23226769
lung cancer; ground-glass opacities; chromosome abnormalities; multi-step progression
15.  Lung cancer mimicking lung abscess formation on CT images 
Patient: Male, 64
Final Diagnosis: Lung pleomorphic carcinoma
Symptoms: Cough • fever
Medication: —
Clinical Procedure: —
Specialty: Oncology
Objective:
Unusual clinical course
Background:
The diagnosis of lung cancer is often made based on computed tomography (CT) image findings if it cannot be confirmed on pathological examinations, such as bronchoscopy. However, the CT image findings of cancerous lesions are similar to those of abscesses.We herein report a case of lung cancer that resembled a lung abscess on CT.
Case Report:
We herein describe the case of 64-year-old male who was diagnosed with lung cancer using surgery. In this case, it was quite difficult to distinguish between the lung cancer and a lung abscess on CT images, and a lung abscess was initially suspected due to symptoms, such as fever and coughing, contrast-enhanced CT image findings showing a ring-enhancing mass in the right upper lobe and the patient’s laboratory test results. However, a pathological diagnosis of lung cancer was confirmed according to the results of a rapid frozen section biopsy of the lesion.
Conclusions:
This case suggests that physicians should not suspect both a lung abscesses and malignancy in cases involving masses presenting as ring-enhancing lesions on contrast-enhanced CT.
doi:10.12659/AJCR.890570
PMCID: PMC4062382  PMID: 24949114
Lung Neoplasms – etiology; Lung Neoplasms – radiography; Lung Neoplasms – surgery
16.  AB 56. Combined large cell neuroendocrine CA with squamous cell CA of the lung 
Journal of Thoracic Disease  2012;4(Suppl 1):AB56.
Background
Presentation of a rare case of lung neoplasia with review of literature.
Patients and methods
We report a case of a 56-year-old male who underwent total excision of his left lung. An intrabronchial lesion that obstructed the main left bronchus was observed in the lower lobe. The lesion was also infiltrating the lung parenchyma and had maximum dimension 6,5cm. Histological examination revealed a malignant tumor, consisted mostly of large cells with irregular shape, abundant cytoplasm and large nuclei. Immunohistochemical results showed that some of the cells were expressing neuroendocrine markers (chromogranine, synaptophysine, CD 56) and the rest of them were expressing markers (p63, Ck5/6) that defined the presence of a squamous cell carcinoma.
Results
According to morphological and immunohistochemical findings, a diagnosis of a combined large cell neuroendocrine carcinoma with squamous cell carcinoma of the lung was confirmed.
Conclusions
A research in international literature showed that this case of combined large cell neuroendocrine carcinoma with squamous cell carcinoma of the lung is uncommon.
doi:10.3978/j.issn.2072-1439.2012.s056
PMCID: PMC3537435
17.  AB 27. Unusual presentation of a pulmonary hamartoma 
Journal of Thoracic Disease  2012;4(Suppl 1):AB27.
Background
Presentation of an unusual case of pulmonary hamartoma.
Materials and methods
Clinical presentation, imaging and outcome.
Results
A male patient, 73 years old, ex-smoker, 80 pack-years, was admitted at the outpatient department, complaining of acute, intense dyspnea, right-sided and retrosternal chest pain for the past few hours and hemoptysis for the past 12 days. Medical history: chronic obstructive airway disease (FEV1: 1.72 L - 63% predicted), carotid and abdominal aortic aneurysm and two temporary ischemic vascular episodes. Chest radiograph showed elevation of the right hemidiaphragm, infiltrates at the right upper and middle lung field and traction of the trachea to the right. Due to resistant hypoxemia (pO2: 49 mmHg, pCO2: 39 mmHg, ph: 7.4 on 30 lt O2/min) he was intubated and put on mechanical ventilation. After intubation his radiograph showed complete atelectasis of the right lung. Computed tomography with i.v. contrast infusion revealed no vascular thrombi, but a thelomatous projection in the lumen of the right main bronchus, causing atelectasis to segments of all the lobes of the right lung. Bronchoscopy was performed, showing a mass occluding the right main bronchus. Two successful attempts were made for partial debulking of the mass bronchoscopically, as the initial oxygenation of the patient was difficult, with an FiO2 of 100%. With a tentative diagnosis of hamartoma, a right upper lobectomy (sleeve resection) was performed (the mass originated from the posterior segment of the upper lobe) and hamartoma was confirmed. Afterwards the patient had pump failure and required tracheostomy and prolonged mechanical ventilation with gradual amelioration. The tracheostomy was finally closed and the patient was released in excellent condition after a two-month hospital stay. Pulmonary hamartomas usually present as an asymptomatic peripheral nodule and are the commonest benign pulmonary nodules (75%). In big series endobronchial localization is less than 6%, while in another study obstructive signs were present in 14%. The present case was unusual in that it presented with respiratory failure requiring intubation, due to the position of the lesion very close to the origin of the right mainstem bronchus.
Conclusions
Even benign pulmonary tumors may mimic an advanced lung carcinoma, so special attention is needed in the diagnostic procedures.
doi:10.3978/j.issn.2072-1439.2012.s027
PMCID: PMC3537420
18.  Methylene Blue-Aided In Vivo Staining of Central Airways during Flexible Bronchoscopy 
The Scientific World Journal  2012;2012:625867.
Background. The early diagnosis of malignant and premalignant changes of the bronchial mucosa remains a major challenge during bronchoscopy. Intravital staining techniques are not new. Previous small case series suggested that analysis of the bronchial mucosal surface using chromoendoscopy allows a prediction between neoplastic and nonneoplastic lesions. Objectives. The aim of the present study was to evaluate chromobronchoscopy as a method to identify malignant and premalignant lesions in the central airways in a prospective manner. Methods. In 26 patients we performed chromoendoscopy with 0.1% methylene blue during ongoing flexible white light bronchoscopy. Circumscribed lesions in central airways were further analyzed by biopsies and histopathologic examination. Results. In the majority of cases neither flat nor polypoid lesions in the central airways were stained by methylene blue. In particular, exophytic growth of lung cancer did not show any specific pattern in chromobronchoscopy. However, a specific dye staining was detected in one case where exophytic growth of metastatic colorectal cancer was present in the right upper lobe. In two other cases, a circumscribed staining was noted in unsuspicious mucosa. But histology revealed inflammation only. Conclusions. In contrast to previous studies, the present findings clearly indicate that chromobronchoscopy is not useful for early detection of malignant or premalignant lesions of the central airways.
doi:10.1100/2012/625867
PMCID: PMC3415176  PMID: 22919343
19.  Relationship between angiogenic squamous dysplasia and bronchogenic carcinoma in patients undergoing white light bronchoscopy 
OBJECTIVE:
To better understand the characteristic morphology of angiogenic squamous dysplasia (ASD) and its association with different types of common bronchogenic carcinomas using routine white light bronchoscopy.
METHODS:
Using a case-control design, 186 formalin-fixed paraffin-embedded blocks of bronchial tissue (136 cases, 50 controls) obtained from patients who underwent routine nonfluorescence bronchoscopy between 2004 and 2005 were studied.
RESULTS:
ASD occurred at a higher frequency in patients with neoplastic lesions compared with those without neoplastic lesions (28 of 136 versus one of 50). ASD was also more prevalent in patients with squamous cell carcinoma compared with other neoplasms. Seventy six per cent of the ASD patients (22 of 29) smoked cigarettes. The morphology of ASD on hematoxylin and eosin- and CD31-stained sections was characterized by prominent microvasculature and capillary projections closely juxtaposed to variable degrees of dysplasia in all of the bronchogenic carcinoma specimens, and to metaplasia in one case in the control group.
CONCLUSION:
ASD is a unique morphological entity that should be considered by pathologists even on bronchoscopic biopsies from patients who undergo white light bronchoscopy. The presence of ASD may represent a risk biomarker of bronchogenic carcinoma in screening programs and in chemoprevention of lung cancer.
PMCID: PMC3418095  PMID: 22679613
Angiogenic squamous dysplasia; Bronchogenic carcinoma; Bronchoscopy; Fluorescence; Immunohistochemistry
20.  Mucoepidermoid Carcinoma of the Lung: A Case Report and Literature Review 
Introduction. Mucoepidermoid carcinoma (MEC) of the lung is a rare form of lung cancer that is classified into low grade and high grade based on histological features. Surgical resection is the primary treatment for low-grade MEC with excellent outcomes, while high-grade MEC is a more aggressive form of malignancy. Clinical Case. We report a case of a 46-year-old woman who presented with dyspnea on exertion. Imaging studies revealed a mass involving the right upper lobe bronchus. Bronchoscopy, surgical resection, and pathological examination revealed a low-grade MEC with tumor-free margins. No adjuvant treatment was given. Discussion. Primary pulmonary MEC is a rare type of lung cancer with only few reported cases. This patient illustrates a typical presentation for low-grade MEC wherein surgical resection is considered curative. In contrast, high-grade MEC is a more aggressive malignancy with a poorer outcome. The role of targeted therapy directed against EGFR or a novel CRTC1-MAML2 fusion protein expressed in some high-grade tumors is yet to be determined.
doi:10.1155/2013/625243
PMCID: PMC3834989  PMID: 24303221
21.  Biomarkers for screening of lung cancer and pre-neoplastic lesions in a high risk Chilean population 
Biological Research  2014;47(1):62.
Background
The mortality of lung cancer (LC), increases each year in the world, in spite of any advances, in development of new drugs to advance stages of LC. The high incidence of LC has been associated with smoking habit, genetic diversity and environmental pollution. Antofagasta region has been reported to have the highest LC mortality rate in Chile and its inhabitants were exposed to arsenic in their drinking water in concentrations as high as 870 μg/L. Non-invasive techniques such as biomarkers (Automatic Quantitative Cytometry: AQC and DR70) and Auto Fluorescence Bronchoscopy (AFB) might be potentially useful as a supplementary diagnostic approach and early detection. Early detection is one of the most important factors to intervene and prevent cancer progression in LC. This is a work of an ongoing prospective bimodality cancer surveillance study in high risk LC volunteers. Enrolment was done in subjects from Antofagasta and Metropolitan regions. In addition, we enrolled subjects who were suspected of having lung cancer. AQC, DR70 and AFB were used as tools in the detection of pre-neoplastic (PNL) and neoplastic lesions (NL).
Results
Half of the samples, classified as suspicious by AFB, were confirmed as metaplasia or dysplasia by histopathology. For LC, DR70 showed a higher sensitivity (95.8%) and specificity (91.9%) than AQC. However, for PNL AQC showed a higher sensitivity (91.9%) than DR70 (27.3%), although both with low PPV values. As a pre screener, both biomarkers might be employed as complementary tools to detect LC, especially as serially combined tests, with a sensitivity of 60% and a PPV of 65.2%. Additionally, the use of parallel combined tests might support the detection of PNL (sensitivity 91.2%; PPV 49.1%).
Conclusion
This work adds information on cellular and molecular biomarkers to complement imaging techniques for early detection of LC in Latin America that might contribute to formulate policies concerning screening of LC. Supported by INNOVA-CORFO, Chile.
doi:10.1186/0717-6287-47-62
PMCID: PMC4335787
Early detection; Biomarkers; Lung cancer
22.  Nodal involvement pattern in resectable lung cancer according to tumor location 
The aim in this study was to define the pattern of lymph node metastasis according to the primary tumor location. In this retrospective cohort study, each of the operable patients diagnosed with lung cancer was grouped by tumor mass location. The International Association for the Study of Lung Cancer nodal chart with stations and zones, established in 2009, was used to define lymph node levels. From 2006 to 2010, 197 patients underwent a lobectomy with systematic nodal resection for primary lung cancer at Chiang Mai University Hospital. There were 123 male and 74 female patients, with ages ranging from 16– 85 years old and an average age of 61.31. Analyses of tumor location, histology type, and nodal metastasis were performed. The locations were the right upper lobe in 63 patients (31.98%), the right middle lobe in 18 patients (9.14%), the right lower lobe in 30 patients (15.23%), the left upper lobe in 55 patients (27.92%), the left lower lobe in 16 patients (8.12%), and mixed lobes (more than one lobe) in 15 patients (7.61%). The mean tumor size was 4.45 cm in diameter (range 1.2–16.5 cm). Adenocarcinoma was the most common histological type, which occurred in 132 cases (67.01%), followed by squamous cell carcinoma in 41 cases (20.81%), bronchiolo alveolar cell carcinoma in nine cases (4.57%), and large cell carcinoma in seven cases (3.55%). Eighteen cases (9.6%) had skip metastasis (mediastinal lymph node metastasis without hilar node metastasis). Adenocarcinoma and intratumoral lymphatic invasion were the predictors of mediastinal lymph node metastases. There were statistically significant differences between a tumor in the right upper lobe and the right lower lobe. However, there were no statistically significant differences between tumors in the other lobes. In conclusion, tumor location is not a precise predictor of the pattern of nodal metastasis. Systematic lymph node dissection is the only way to accurately determine lymph node status. Further studies are required for evaluation and conclusions.
doi:10.2147/CMAR.S30526
PMCID: PMC3379857  PMID: 22740775
lung cancer; nodal metastasis
23.  Cell migration leads to spatially distinct but clonally related airway cancer precursors 
Thorax  2014;69(6):548-557.
Background
Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related.
Methods
Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship.
Results
We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years.
Conclusions
Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.
doi:10.1136/thoraxjnl-2013-204198
PMCID: PMC4033139  PMID: 24550057
Lung Cancer; Airway Epithelium
24.  Primary pulmonary cavitating carcinomas 
Thorax  1973;28(3):354-366.
A primary lung cancer can produce a cavity in three ways. The first is `cavitary necrosis' due to breakdown of the growth itself. The second is `stenotic abscess' due to infection and breakdown of the lung parenchyma distal to bronchial obstruction caused by the growth. The third type is `spill-over abscess'.
In the present series, necrosis and cavitation were observed in 100 cases out of a total of 632 primary bronchial carcinomas seen at the London Chest Hospital from July 1967 to June 1970. There were 91 males and nine females with an average age of 58·45 years. All except one smoked very heavily and had considerable symptoms. The size of the cavities ranged from 1 to 10 cm and their wall thickness from 0·5 to 3 cm. They were single in 92 cases and multiple (up to four) in eight. In 42 cases, the cancerous cavitation was central, in 38 intermediate, and in 20 peripheral. The segments most frequently affected were the apicoposterior segment of the left upper lobe and the superior segment of the left lower lobe. For descriptive purposes, these cavitating carcinomas were also divided into six broad groups on the basis of radiological and pathological correlations. Neoplastic cells in the sputum were found in 64 cases. Bronchoscopy revealed growth in 42 cases and biopsy was positive in 48. The main microscopic feature was vascular invasion of medium-sized muscular arteries and veins found in the vicinity of every cavitating bronchial carcinoma. Invasion along with tumour plugging of the vessels was observed in 75 cases and thrombosis alone in 55 cases. There were 82 squamous-cell carcinomas, 11 undifferentiated carcinomas of large polygonal-cell type, and seven adeno-alveolar cell carcinomas.
The single most important and noteworthy feature in the present series was that oat-cell carcinoma hardly ever undergoes necrosis. Out of a total of 95 cases observed, only three showed necrosis, and this was minimal and characteristically devoid of cavitation. In oat-cell carcinoma vascular invasion and tumour plugging was not observed, though all showed rapid growth and most of them blocked the lobar bronchi completely. In the light of the present study, the main factors responsible for tumour necrosis were found to be gradual bronchial obstruction and associated vascular involvement, though in many cases an inherent propensity of the tumour played a major role.
Images
PMCID: PMC470041  PMID: 4353362
25.  Characteristics of chromate workers' cancers, chromium lung deposition and precancerous bronchial lesions: an autopsy study. 
British Journal of Cancer  1994;70(1):160-166.
The characteristics of lung cancers induced by inhaled chromate were studied in 13 consecutive autopsies on male ex-chromate workers. In addition to histopathology, we examined: (1) the relationship between the occurrence of lung cancer and the amount of chromium (Cr) deposited in the lung as determined by atomic absorptiometry and (2) the chronological changes in five precancerous lung lesions followed by bronchoscopy till death. Twenty-one cancers were identified, including 16 lung tumours observed either during follow-up or at autopsy. Of these 16 tumours, 13 were found in six subjects, implying a high frequency of multiple cancers. Eleven (69%) out of the 16 tumours were of squamous cell type (including carcinoma in situ), this being twice as frequent as in age-matched controls. A further characteristic was predominance in the central part of lung (69%). The lung Cr burden was very much higher [40-15,800 micrograms g-1 (dry)] in patients with lung tumours than in those without (8-28 micrograms g-1). Five of the precancerous lesions followed by bronchoscopy originated at bronchial bifurcations. Four of these cases showed a return to normal histology at autopsy even without therapy, and the other did not progress.
Images
PMCID: PMC2033298  PMID: 8018529

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