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Clinical Meetings at RH Year 2010

2010 Sep/Oct - New Kids on the Block?

Dr Wai Ka Yan and Dr Wong Wing Ching; Department of Medicine, Kwong Wah Hospital



Case History
The patient was a 36 year-old non-smoker with no family history of lung cancer, complained of insidious onset of breathlessness and dry cough for weeks. Physical examination showed right pleural effusion. His CT thorax showed an enhanced soft tissue lesion (2.2cm x 1.9cm) at the anterior segment of right upper lobe (Fig. 1a & 1b). There were also another 0.5cm enhancing soft tissue nodule at the lateral segment of right middle lobe, pre-tracheal lymphadenopathy and collapse consolidation of basal segment of right lower lobe. Sputum was not available for investigation. Diagnostic thoracocentesis yielded heavily blood-stained pleural fluid. Closed pleural biopsy was negative but the pleural fluid cytology showed metastatic adenocarcinoma. The final diagnosis was advanced bronchogenic adenocarcinoma.


In order to get a better histological sample of the tumour for EGFR activating mutation direct DNA sequencing study, various options of diagnostic procedures have been considered. These include repeating closed pleural biopsy but its yield remains low. Medical pleuroscopy was then not available in our hospital. The yield of bronchoscopic transbronchial lung biopsy is relatively low (~40%) given the peripheral location of the tumour. Although its yield could be improved with fluoroscopic guidance, we do not perform fluoroscopy in our hospital. CT-guided transthoracic needle aspiration can be associated with complications such as iatrogenic pneumothorax (~15-43%) and haemorrhage (~5-17%), while its yield can vary and depend very much on the experience of radiologists. VATS open lung biopsy would be the most accurate procedure but it is more invasive and costly. It was not chosen because of the confirmed advanced staging of the disease.With the availability of endobronchial ultrasound (EBUS), we have explored the clinical application of miniprobe radial


EBUS guided transbronchial lung biopsy. With the guidance of radial EBUS probe through the working channel of a regular therapeutic bronchoscope, a lesion measured 1.67cm x 1.89cm (Fig. 2) was located distal to the RB3a subsegment. Guidesheath guided brush cytology and transbronchial biopsy yielded adenocarcinoma. Subsequent mutation study showed a 15 bp deletion (2235-2249) of the exon 19, compatible with an exon 19 EGFR activation mutation.

The patient was referred to receive palliative oncological treatment. First-line chemotherapy consisted of gemcitabine and cisplatin was offered because of his good performance status. Target therapy (tyrosine kinase inhibitor) was reserved as 2nd line treatment should his 1st line chemotherapy failed.

History of radial miniprobe EBUS (R-EBUS)
Hϋrter et al from Germany first demonstrated the possible utility of radial EBUS in the respiratory system for diagnostic purpose.1 He could identify 69/74 (93%) of all tumours, in which 19/26 (73%) were bronchoscopically invisible because of their peripheral locations. The progress of development however remained slow because of the hindrance of air-filled nature of respiratory system to ultrasound (US) signal. It was not until 1999 when Prof. Becker of the University of Heidelberg in Germany introduced his first prototype water-filled balloon incorporated radial EBUS to revolutionize its practical use in diagnostic and therapeutic bronchology (Fig. 3a & Fig. 3b).2 With improvement of ultrasound technology, the frequency of ultrasound signal has increased from 7.5 MHz (prototype) to 20-30 MHz with much better signal resolution for the practical use. External diameters of probes have also become slimmer from the original prototype to the current 1.4-1.8mm for more versatile peripheral applications.


Application of R-EBUS
Central airway tumours
1. Early lung cancer detection and localization
2. Determination of tumour extension, hence guiding therapeutic treatment
3. Assistance in therapeutic bronchology, e.g. palliative endobronchial stent placement, tumour debridement, etc.
Peripheral lung lesions
1. Localization of peripheral lesions and guide bronchoscopic diagnostic procedure, e.g. transbronchial lung biopsy, brush cytology, etc.
2. Ultrasonographic features to predict neoplastic (vs. benign) lesions
3. Improving the diagnostic yield of pulmonoary TB



Central airway disease
Seven echogenic layers of cartilaginous part and 3 echogenic layers of membranous part of tracheobronchial tree can normally be identified with R-EBUS (Fig 4a & 4b). The 3rd-5th layers denote the cartilage layers by which destruction determine invasion by central airway tumours (Fig 4c). Kurimoto et al. demonstrated that EBUS findings correlated well with histological findings in all 24 but 1 of cases, and the only false positive case was lymphocytic infiltration rather than tumour invasion of adventitia.3 Herth et al. also showed similar results in 56 patients. The false negative lesions were all located at the trachea. The small size of radial probe and the limited contact of balloon with tracheal wall could have been the reasons. EBUS findings were highly correlated with surgical findings (r=0.89, p<0.01), and with accuracy 94%, sensitivity 89%, specificity 100%, which compared favourably with CT (r=0.06, p=0.4), with accuracy 51%, sensitivity 75%, specificity 28% respectively.4

With the use of R-EBUS in detecting tumour invasion, it helps in deciding whether bronchscopic therapy such as photodynamic therapy (PDT), cryotherapy and laser therapy, or otherwise surgical resection would be the more appropriate treatment. Surgical resection could be considered to be “wasteful” in patients with lobectomy.5,6 That would particularly be important in those frail patients, in whom surgery is contraindicated and in whom conservation of lung tissue is paramount to maintain reasonable quality of life. Acceptable clinical outcomes with bronchoscopic treatment can be obtained, as long as the lesions can be correctly diagnosed as “early non-invasive” by R-EBUS. Miyazu et al. showed a promising clinical remission rate of 100% in 9 patients with EBUS proven early non-invasive lesions treated by PDT, with a median follow-up of 32+/-14 months.7

Peripheral lung lesions
The increased prevalence of adenocarcinoma might imply more peripheral pulmonary lesions in the clinical presentation.8,9 Bronchoscopic transbronchial brush cytology and lung biopsy with or without fluoroscopy is the conventional diagnostic procedure. The diagnostic yield depends on the size, location and presence of CT “bronchus sign” of the lesions. For solitary pulmonary nodule (SPN) with size < 2cm, diagnostic yield was around 33%, with a range of 10-42% across various studies. SPNs at upper lobes are less likely to be diagnosed due to the required acute angulation of diagnostic instruments. The presence of CT “bronchus sign” doubled the diagnostic rate from 30% to 60% in some studies.10 Recent advances such as ultrathin bronchoscope, electromagnetic (EM) navigation and virtual bronchoscopy have also been shown to improve overall yield for SPN diagnosis.

Transthoracic needle aspiration (TTNA) under CT guidance is another conventional investigation. Its sensitivity ranges from 65-94%, with specificity 50-88%, false negative rate 20-30% and negative predictive value of 50-60%. The non-diagnostic rate has been reported as 4-41%, and up to 44% for benign nodules due to small amount of tissue obtained to achieve a definitive pathological diagnosis.11 Pneumothorax, the commonest complication which occurs in 15-43%, is usually small and requires no intervention. Risk factors include low FEV1, long needle path length (>2cm), small target lesion size, oblique or trans-fissural puncture, punctures through aerated lung (50% vs. pleural-based lesions 15%). However, type and size of needles, number of punctures and needle dwelling time have not been found to be related to pneumothorax. Haemorrhage (5-17%) is usually mild, but severe haemorrhage can occur. Risk factors include centrally located lesions (near great vessels), deep lesions (>2cm from pleura), proximity of large vessels near puncture site, pulmonary hypertension, chronic renal failure, concurrent aspirin use and use of core biopsy needle. Other less common complications include cardiac tamponade, air embolism and needle track tumour implantation. The commonest causes of death are pulmonary haemorrhage and air embolism, with an overall procedure related mortality of 0.02%.12-16

Studies of R-EBUS have shown impressive diagnostic rates in SPNs, with yields of 40-70% and 60-80% in lesions of <2cm and <3cm respectively, and an overall yield of 60-80%.17 In UK, a NICE guideline on radial EBUS transbronchial biopsy for peripheral lung lesions was adopted in early 2010. The use of R-EBUS for biopsy of SPNs has been combined with other tools such as curettage, guide-sheath, transbronchial needle, fluoroscopy, EM navigation and virtual bronchoscopy. Overall diagnostic yield is higher than the usual bronchoscopic transbronchial lung biopsy, especially in lesions <3cm.18.19 It is particularly helpful for those small lesions which are sub-optimally demonstrated under fluoroscopy. In a study by Herth et al. of 54 patients with fluoroscopically “invisible” SPNs (size 2.2+/-0.7cm), R-EBUS prevented 17% of cases from undergoing otherwise unnecessary surgical diagnostic procedures.20 It was also shown to be superior to TTNA for non-pleural based SPNs, especially when CT “bronchus sign” is present. Complications in terms of pneumothorax (1.4% vs. 22.3%) and haemorrhage (0% vs. 3.3-9.1%) were shown to lower when compared with TTNA.21

Summary
R-EBUS might emerge to be a promising diagnostic tool in the diagnosis of SPNs. It is especially useful for those non-pleural based SPNs, SPNs < 2cm which are likely to be fluoroscopically invisible and possibly lesions with predominant ground glass opacities which require more representative pathological samples for specific histologic diagnosis.

References
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