The diagnosis of lung cancer in the era of interventional pulmonology.

Advances in bronchoscopic and other interventional pulmonology technologies have expanded the sampling procedures pulmonologist can use to diagnose lung cancer and accurately stage the mediastinum. Among the modalities available to the interventional pulmonologist are endobronchial ultrasound-guided transbronchial needles aspiration (EBUS-TBNA) and transoesophageal bronchoscopic ultrasound-guided fine-needle aspiration (EUS-B-FNA) for sampling peribronchial/perioesophageal central lesions and for mediastinal lymph node staging, as well as navigational bronchoscopy and radial probe endobronchial ultrasound (RP-EBUS) for the diagnosis of peripheral lung cancer. The role of the interventional pulmonologist in this setting is to apply these procedures based on the correct interpretation of clinical and radiological findings in order to maximise the chances of achieving the diagnosis and obtaining sufficient tissue for molecular biomarker testing to guide targeted therapies for advanced non-small cell lung cancer. The safest and the highest diagnosis-yielding modality should be chosen to avoid a repeat sampling procedure if the first one is non-diagnostic. The choice of site and biopsy modality are influenced by tumour location, patient comorbidities, availability of equipment and local expertise. This review provides a concise state-of-the art account of the interventional pulmonology procedures in the diagnosis and staging of lung cancer.

Application of 18F-FDG PET-CT in the management of pulmonary nodule and mass - a pictorial review.

BACKGROUND: Lung cancer is one of the leading causes of cancer-related mortality worldwide. Pulmonary nodules are commonly encountered in clinical practice because of the recent implementation of low-dose CT lung screening programme, incidental finding on cardiac CT or CT for nonthoracic related disease. 18F-FDG PET-CT plays an important role in the management of pulmonary nodules. METHODS: In this pictorial review, we present six different scenarios of using 18F-FDG PET-CT in the management of suspicious pulmonary nodule or mass. The advantages and limitations of 18F-FDG PET-CT and Herder model are discussed. RESULTS: 18F-FDG PET-CT with risk assessment using Herder model provides added value in characterising indeterminate pulmonary nodules. Besides, 18F-FDG PET-CT is valuable to guide the site of biopsy and provide accurate staging of lung cancer. CONCLUSION: To further improve its diagnostic accuracy, careful history taking, and CT morphological evaluation should be taken into consideration when interpreting 18FFDG PET-CT findings in patients with these nodules.

Anaplastic lymphoma kinase (ALK) mutations in patients with adenocarcinoma of the lung.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death. Approximately 2-16% of NSCLC patients with wild-type epidermal growth factor receptor (EGFR) harbour anaplastic lymphoma kinase (ALK) mutations. Both EGFR and ALK mutations occur most commonly in Asian patients with NSCLC. As targeted therapy is available for NSCLC patients with these mutations, it is important to establish reliable assays and testing strategies to identify those most likely to benefit from this therapy. MATERIALS AND METHODS: Patients diagnosed with adenocarcinoma of the lung between 2010 and 2014 were tested for EGFR mutations. Of these, 92 cases were identified as EGFR wild type and suitable candidates for ALK testing utilising immunohistochemistry and the rabbit monoclonal antibody D5F3. The reliability of the IHC was confirmed by validating the results against those achieved by fluorescence in situ hybridisation (FISH) to detect ALK gene rearrangements. RESULTS: Twelve (13%) cases were positive for ALK expression using immunohistochemistry. Of the 18 evaluable cases tested by FISH, there was 100% agreement with respect to ALK rearrangement/ALK expression between the assays, with 11 cases ALK negative and 7 cases ALK positive by both assays. ALK tumour expression was significantly more common in female compared to male patients (29.6% vs. 6.2%, P < 0.001), detected exclusively in patients that had never smoked (P < 0.001) and more frequently in metastases (22.7%) than in primary tumours (10%) (P = 0.047). CONCLUSIONS: Detection of ALK expression by IHC is reliable and the most practical way of identifying NSCLC patients likely to benefit from crizotinib treatment.

First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study.

BACKGROUND: The phase III, randomized, open-label ENSURE study (NCT01342965) evaluated first-line erlotinib versus gemcitabine/cisplatin (GP) in patients from China, Malaysia and the Philippines with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0-2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP [G 1250 mg/m(2) i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m(2) i.v. day 1, (3-weekly cycle) for up to four cycles]. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively [hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22-0.51; log-rank P < 0.0001]. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63-1.31; log-rank P = .607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment-related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade ≥3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP. CONCLUSION: These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965).

Prevalence of bronchial asthma among orang asli in peninsular malaysia.

A survey was carried out to determine the prevalence of bronchial asthma and their contributing risk factors among Orang Asli subgroups living in Malaysia using IUATLD questionnaire and spirometry without being discriminatory towards age or gender. Of the 1171 distributed questionnaires, 716 (61.1%) comprising of 62.7% Semai Pahang, 51.3% Temiar, 74.2% Mah Meri, 65.6% Semai Perak, 53.6% Temuan, 53.8% Semelai, 61.1% Jakun and 67.4% Orang Kuala subgroups completed their questionnaire and were included in the data analysis. Participants comprised 549 (76.7%) children and 167 (23.3%) adults, age between 1 to 83 years old, 304 (42.5%) males and 412 (57.5%) females. The overall prevalence of bronchial asthma was 1.4% of which 1.5% was children, 1.3% adults, 1.0% male and 1.7% female, respectively. Of the 8 subgroups surveyed, 5 out of 10 confirmed asthma cases were Semai Pahang, followed by 3 cases among Mah Meri, and one case each among Temuan and Semai Perak subgroups, respectively. This study also demonstrated that the prevalence of self-reported and confirmed bronchial asthma tend to be higher among those who had close contact with pets, smoking individuals and among those who had a family history of asthma.

Diagnostic yield of flexible bronchoscopic procedures in lung cancer patients according to tumour location.

INTRODUCTION: This study aims to determine whether the diagnostic yield of flexible bronchoscopy sampling procedures in patients with lung cancer was dependent on tumour location. METHODS: A retrospective analysis was conducted on the diagnostic yield of bronchial washing (BW), endobronchial biopsy (EBB), bronchial brushing (BB), bronchoalveolar lavage (BAL), blind brushing (B) and transbronchial biopsy (TBB) specimens obtained at fibre-optic bronchoscopy for patients with lung cancer. RESULTS: Of 503 patients who underwent fibre-optic bronchoscopy examination, BW, EBB, BB, BAL, B and TBB were performed on 254, 325, 67, 155, 70 and 54 patients, respectively. For patients with bronchoscopically-visible tumours, BW, EBB and BB yielded diagnostic specimens for lung cancer in 28.3 percent, 77.5 percent and 53.7 percent of patients, respectively. For patients whose tumours were not visible bronchoscopically, BAL, B and TBB yielded diagnostic specimens for lung cancer in 35.5 percent, 22.9 percent and 31.5 percent of patients, respectively. EBB was less likely to be diagnostic in patients with tumours in the middle or lingular lobe bronchi. The diagnostic yields of all the other sampling techniques were not influenced by the location of the bronchoscopically-visible or non-visible tumours. CONCLUSION: The diagnostic yields of bronchoscopic sampling procedures were dependent on tumour visibility during bronchoscopy and location of bronchoscopically-visible tumours.

Tracheobronchial stenting is safe and effective in relieving upper airway obstruction.

Many studies have shown that tracheobronchial stenting is effective in relieving respiratory distress secondary to major airway obstruction due to lung or oesophageal cancer. A retrospective review on the benefits and complications of self-expandable metallic stent (SEMS) insertion through flexible bronchoscopy for the palliative treatment of upper airway obstruction in University Malaya Medical Centre was performed. Ten patients underwent this procedure. Relief of dyspnoea was immediate following stent insertion in all patients. Stent migration occurred in one patient and three patients had restenosis of the central airway. We conclude that tracheobronchial stenting via flexible bronchoscopy is feasible and safe.

Pleural effusions: role of commonly available investigations.

INTRODUCTION: Previous studies have reported high rates of undetermined causes of pleural effusions. We aimed to find out the proportion of pleural effusions in which the aetiology is uncertain despite commonly available investigations. METHODS: A prospective study was carried out at the University of Malaya Medical Centre from May 2001 to January 2002. All patients with pleural effusion admitted to the medical wards and non-medical wards during that period were included in the study. RESULTS: Of 111 patients with pleural effusion, malignancy was the commonest cause of pleural effusion (34.2 percent), followed by tuberculosis (22.5 percent) and parapneumonic effusions (18.9 percent). There were only two patients (1.8 percent) with undetermined cause despite extensive investigations. Carcinoma of the lung was the commonest cause of malignant effusions and bronchoscopic biopsy gave the highest yield of histological diagnosis (66 percent), followed by pleural fluid cytology (59 percent) and pleural biopsy (50 percent). The combination of these three procedures increased the diagnostic yield to 96 percent. In tuberculous pleural effusion, pleural fluid staining for acid-fast bacilli was negative in all cases but mycobacterial culture was positive in 24 percent of cases while pleural biopsy gave a better yield of 68.8 percent. Examination of sputum and bronchoalveolar lavage specimens confirmed the diagnosis of tuberculosis in 40 percent of cases. A combination of these investigations yielded the diagnosis in 92 percent of patients with tuberculous effusion. CONCLUSION: Malignancy is the commonest cause of pleural effusion, followed by tuberculosis and pneumonia, in patients treated in a teaching hospital in Malaysia. The number of undetermined causes could be minimised with a combination of readily-available and established investigations.

Serum cancer antigen 125 in patients with pleural effusions.

We studied the prevalence of raised serum CA125 in patients with pleural effusions and explored factors affecting its level. Sixty four patients with benign effusions and 36 patients with malignant effusions admitted to the University Malaya Medical Centre from May 2001 to January 2002 were included in the study. There were no significant differences in age, gender and ethnicity of the patients with benign and malignant effusions. There was also no difference in the frequency of the side of pleural effusion between the two groups but compared to benign effusions, a higher proportion of malignant effusions was moderate to large in size (66% versus 39%, p = 0.011). Serum CA125 levels were above 35U/dL in 83.3% and 78.1% of patients with malignant and benign effusions, respectively (p = 0.532). All patients with underlying malignancy and 95.3% of patients with benign effusions had pleural fluid CA125 levels above 35U/dL (p = 0.187). The median levels of CA125 were higher in the pleural fluid than in the serum in all aetiological groups. Higher serum CA125 levels were more likely to be found in patients with moderate to large effusions (p = 0.015), malignant effusions (p = 0.001) and in female patients (0.016). Serum CA125 level showed significant correlation with pleural fluid CA125 level (r = 0.532, p < 0.001) but not with pleural fluid total white blood cell count (r = -0.092, p = 0.362), red blood cell count (r = -0.082, p = 0.417) and lactate dehydrogenase level (r = 0.062, p = 0.541). We conclude that serum CA125 is commonly elevated in patients with benign and malignant pleural effusions.

Sensitization profiles of Malaysian and Singaporean subjects to allergens from Dermatophagoides pteronyssinus and Blomia tropicalis.

BACKGROUND: The house dust mites Dermatophagoides pteronyssinus (Der p) and Blomia tropicalis (Blo t) are the most common house dust mite species in Southeast Asia. To date, there have only been a few studies on the sensitization profile of the general populations in Southeast Asia to house dust mites. The aim of this study was to determine the profiles of Der p and Blo t sensitization among Singaporean and Malaysian subjects. METHODS: Enzyme-linked immunosorbent assay was used to detect specific IgE to Der p and Blo t mite crude extracts as well as purified Der p 1, Der p 2 and Blo t 5 allergens. Sera used were from 229 Singaporean subjects (124 with rhinitis, 105 without rhinitis) and 143 Malaysian subjects (94 adults and 49 children with asthma). RESULTS: The sensitization profile of rhinitis subjects to the dust mite allergens used in this study was as follows: Blo t extract positive: 91/124 (73%); Blo t 5 positive: 62/124 (50%); Der p extract positive: 61/124 (49%); Der p 1 positive: 53/124 (43%); Der p 2 positive: 45/124 (36%). The nonrhinitis subjects' sensitization profile was as follows: Blo t extract positive: 60/105 (57%); Blo t 5 positive: 24/105 (23%); Der p extract positive: 38/105 (36%); Der p 1 positive: 14/105 (13%); Der p 2 positive: 17/105 (16%). The study of Malaysian asthmatic adults showed that 39% of them were sensitized to Der p 1, 32% to Der p 2 and 37% to Blo t 5. Among the asthmatic children, sensitization to Blo t 5, Der p 1 and Der p 2 was 90, 57 and 39%, respectively. CONCLUSION: This study clearly revealed that dual sensitization to B. tropicalis and D. pteronyssinus is common in the general populations of Singapore and Malaysia. Sensitization to Blo t 5 is more prevalent than to Der p 1 and Der p 2.

Differences in pleural fluid characteristics, white cell count and biochemistry of tuberculous and malignant pleural effusions.

Tuberculosis and malignancy are two common causes of exudative pleural effusions. In this retrospective study of 52 patients with tuberculous pleural effusions and 32 patients with malignant effusions, the median age of patients with malignant effusions (68.5 years) was older than that of patients with tuberculous effusions (34.5 years) (p < 0.001). Both types of effusion occurred more frequently on the right side and there was no difference between them in terms of right-sided dominance. A higher percentage of patients with malignant pleural effusions (44%) presented with large effusions than patients with tuberculous effusions (12%) (x2 = 11.33, p = 0.001). A higher proportion of patients with tuberculous effusion had lymphocyte predominant effusions and tuberculous effusions had higher lymphocyte percentage, lower red cell count, and higher protein content. However, there was considerable overlap of these characteristics of both types of effusions.

Causes of pleural exudates in a region with a high incidence of tuberculosis.

OBJECTIVE: To define the causes of exudative pleural effusions in our region. METHODOLOGY: A retrospective study was performed on consecutive patients with exudative pleural effusion seen in our hospital during a 4-year period. RESULTS: Of 186 patients with a mean age (+/- SD) of 51.2 (+/- 19.2) years with exudative pleural effusions, 131 (70.4%) were males and 55 (29.6%) were females. The most frequent cause of exudative pleural effusions was tuberculosis (44.1%), followed by malignancy (29.6%). The majority (94.5%) of malignant pleural effusions were due to lung cancer. Apart from a patient with bilateral pleural effusions due to cryptococcosis, patients with tuberculous pleural effusion (mean age (+/- SD), 39.7 (+/- 17.5)) were significantly younger than the rest (P < 0.05). Tuberculous effusions were most frequent in the first five decades (60/82, 73.2%) and were the most common type of pleural effusion, accounting for 60 (69.8%) of 86 cases, in this age range. Malignant effusions were more frequent among the older age groups, 74.5% (41/55) of patients with malignant effusions being older than 50 years. Most types of pleural effusions showed a preference for the right side. Of the 44 cases of large effusions, 28 (63.6%) were caused by malignancy. CONCLUSIONS: In our region with a high incidence of tuberculosis, the most frequent cause of pleural exudates is tuberculosis followed by malignancy, particularly lung cancer.

Lung cancer in patients younger than 40 years in a multiracial Asian country.

OBJECTIVE: This study aimed to determine whether the clinicopathological features of lung cancer in patients younger than 40 years differ from that of older patients in an Asian country. METHODOLOGY: We undertook a review of the clinicopathological data of all patients with confirmed primary lung cancer at the Department of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia, from October 1991 to September 1999. RESULTS: Of the 580 patients with lung cancer, 36 (6.2%; 23 males, 13 females) were 21-39 years old at diagnosis. The percentage of people who had never smoked was higher among the younger patients (58.3% vs 19.1%, P < 0.001). Although adenocarcinoma was the most common cell type in both groups, its incidence was higher in the younger patients (24/36 (66.7%) vs 228/544 (41.9%), P = 0.007). The mean World Health Organization performance status at presentation was worse in the younger patients (2.4 vs 2, P = 0.007). In the case of non-small cell lung cancer, all the younger patients presented with either stage IIIb or metastatic disease compared to 77.2% of the older patients (P < 0.001). CONCLUSIONS: Younger lung cancer patients were more likely than older patients to have never smoked, to have adenocarcinoma, and to present with poorer performance status and with more advanced-stage non-small cell lung cancer.

Localised nodular pulmonary amyloidosis in a patient with sicca syndrome.

A 52 year old Chinese woman with a 25 year history of sicca syndrome (primary Sjogrens syndrome) was investigated for 3 episodes of haemoptysis. Clinical examination was unremarkable except for the presence of dry eyes and xerostomia. Computed tomography of the chest revealed a lobulated mass in the posterior basal segment of the left lower lobe. Histopathological examination of this resected nodule confirmed the diagnosis of nodular amyloidosis. The normal radiolabelled serum amyloid P component scintigraphy and the absence of monoclonal plasma cell dyscrasia in the bone marrow strongly support the diagnosis of localised nodular pulmonary AL amyloidosis in this patient. Nodular pulmonary amyloidosis can be associated with sicca syndrome and often simulates bronchogenic carcinoma, bronchiectasis or pulmonary tuberculosis.

Pulmonary siderosis in an arc welder.

An asymptomatic subject with radiographic changes due to welders' siderosis is described. This condition has not been well recognized and described in our community. Siderosis of the lung is generally considered to be a benign condition not associated with respiratory symptoms. However, recent reports have associated welding with various disorders of pulmonary function as well as lung cancer. There is a need for future epidemiological studies to better define the risk of long term welding.

Massive pleural effusions in cryptococcal meningitis.

Cryptococcal infection uncommonly presents with pulmonary manifestations and even more rarely so as massive bilateral effusions. Pleural involvement is usually associated with underlying pulmonary parenchymal lesions and is unusual while on antifungal therapy. We report a patient with cryptococcal meningitis who, while on intravenous 5-flucytosine and amphotericin B, developed life-threatening bilateral massive pleural effusions with evidence of spontaneous resolution, consistent with prior hypothesis of antigenic stimulation as the cause of pleural involvement.

Giant cell arteritis presenting as chronic cough and prolonged fever.

A 62-year-old man presented with a 3-month history of chronic non-productive cough and unexplained fever. Further questioning revealed that he had headaches and myalgia. Bilateral thickened temporal arteries were noted on physical examination. The erythrocyte sedimentation rate was 96 mm in 1 h. A biopsy specimen of the left temporal artery showed inflammatory changes consistent with the diagnosis of giant cell arteritis. Commencement of prednisolone resulted in rapid and dramatic resolution of his symptoms. Physicians should be aware of respiratory symptoms in patients with giant cell arteritis in order to avoid delay in diagnosis and therapy of this condition.