Small lung nodule is a common problem in pulmonary practice. The definition of a classical solitary pulmonary nodule is a single, spherical, well-circumscribed, radiographic opacity less than or equal to 30 mm in diameter that is completely surrounded by aerated lung and is not associated with atelectasis, hilar enlargement, or pleural effusion. Ideally, the goal of diagnosis and management is to promptly bring to surgery all patients with operable malignant nodules while avoiding unnecessary thoracotomy in patients with benign disease. In fact, causes of solitary pulmonary nodules can be benign or malignant. In order to diagnose causes of solitary pulmonary nodules, we can use many different methods, including clinical symptoms, radiographic features, liquid biopsy, bronchoscopy, CT-guided fine-needle aspiration biopsy and surgery. Each method has its own value. It is very meaningful if we can diagnose these causes early. Based on these results, doctors can determine the strategy to manage disease.
Journal of military pharmaco-medicine no7-2019 DIAGNOSIS OF SOLITARY PULMONARY NODULES: AN UPDATED REVIEW Dao Ngoc Bang1; Ta Ba Thang1; Do Quyet2 SUMMARY Small lung nodule is a common problem in pulmonary practice The definition of a classical solitary pulmonary nodule is a single, spherical, well-circumscribed, radiographic opacity less than or equal to 30 mm in diameter that is completely surrounded by aerated lung and is not associated with atelectasis, hilar enlargement, or pleural effusion Ideally, the goal of diagnosis and management is to promptly bring to surgery all patients with operable malignant nodules while avoiding unnecessary thoracotomy in patients with benign disease In fact, causes of solitary pulmonary nodules can be benign or malignant In order to diagnose causes of solitary pulmonary nodules, we can use many different methods, including clinical symptoms, radiographic features, liquid biopsy, bronchoscopy, CT-guided fine-needle aspiration biopsy and surgery Each method has its own value It is very meaningful if we can diagnose these causes early Based on these results, doctors can determine the strategy to manage disease * Keywords: Solitary pulmonary nodule; Diagnosis Causes and proportion of solitary pulmonary nodules The definition of a classical solitary pulmonary nodule (SPNs) is a single, spherical, well-circumscribed, radiographic opacity less than or equal to 30 mm in diameter that is completely surrounded by aerated lung and is not associated with atelectasis, hilar enlargement, or pleural effusion [1] Causes of SPNs are very variety, with main groups: benign or malignant ones (table 1) The estimated prevalence of each etiology varies among different populations Even among screening studies of smokers who are at increased risk of malignancy, the number of malignant nodules is small Among 12,029 nodules found in a large Canadian study, only 144 (1%) were malignant [2] 103 Military Hospital Vietnam Military Medical University Corresponding author: Dao Ngoc Bang (bsdaongocbang@yahoo.com.vn) Date received: 24/07/2019 Date accepted: 23/08/2019 156 Journal of military pharmaco-medicine no7-2019 Table 1: Differential diagnosis of SPNs [2] Group Diseases Infectious granuloma (atypical histoplasmosis, tuberculosis) Benign Malignant Proportion mycobacteria, coccidioidomycosis, 80% Hamartoma 10% Arteriovenous malformation; intrapulmonary lymph node; sarcoidosis Rare Adenocarcinoma 60% Squamous cell carcinoma 20% Solitary metastasis (breast, colon, kidney) 10% Small cell carcinoma 4% Carcinoid tumor Rare Extranodal lymphoma Rare Characteristics of each cause are extremely different, including clinical symptoms and paraclinical changes Depending on the characteristics of SPNs, doctors should apply some suitable methods in diagnosis and management Diagnosis of SPNs * Characteristics of risk factors: The probability of malignancy can be assessed clinically or by quantitative predictive models as falling into of risk categories: very low probability (less than 5%), low/moderate probability (5% to 65%), or high probability (greater than 65%) The most commonly used model estimates the probability of malignancy using six independent predictors: smoking history, older age, history of extrathoracic cancer more than five years before nodule detection, nodule diameter, spiculation presence, and upper lobe location An online calculator is available at http://reference.medscape.com/calculator/ solitary-pulmonary-nodule-risk [3] Table 2: Calculating the malignancy probability of a pulmonary nodule [3] Predictors Value Age Patient's age in years Cancer history 1: if patient has a history of extrathoracic cancer diagnosed more than five years before nodule detection (otherwise = 0) Diameter Diameter of the solitary pulmonary nodule in mm Location 1: if nodule is located in the upper lobe (otherwise = 0) Smoking history 1: if patient is a current or former smoker (otherwise = 0) Spiculation 1: if spiculation is present (otherwise = 0) 157 Journal of military pharmaco-medicine no7-2019 * Radiographic features and PET/CT: Incidentally found SPNs are most commonly discovered on CT (computed tomography) scans Although some may be seen on chest radiographs, a CT-scan affords superior detail for evaluating specific characteristics of the nodule Of particular importance is a thorough review of all previous imaging to assess both changes in size and the rate of change over time Numerous studies had demonstrated that increasing nodule size corresponding with increasing risk of malignance: a nodule smaller than mm, less than 1% malignancy risk; a nodule of - mm, - 6% malignancy risk; a nodule of 10 - 20 mm, 18% malignancy risk; a nodule 20 mm or larger, more than 50% malignancy risk Signs of growth on serial imaging are highly suggestive of malignancy The growth rate of an SPN is also used to evaluate the potential for malignancy, with most malignancies doubling in volume between 20 and 400 days A solid SPN that has been stable for more than years is likely to be benign, as is a subsolid nodule that has been stable for more than years Attenuation of the nodule on CT imaging may be characterized as solid or subsolid, with subsolid lesions further divided as pure subsolid and part solid Although solid lesions are more common, subsolid lesions are more likely to be malignant [4, 6] Table 3: Radiologic features suggested benign or malignant SPNs [4] Radiologic features Suggests benign nodule Suggests malignant nodule Smooth Irregular or spiculated Concentric, central, or popcorn pattern Typically noncalcified or eccentric calcification Solid Nonsolid, ground-glass Less than one month or more than one year One month to one year < mm > 10 mm Border Calcification Density Doubling time Size CT examinations of the thorax performed to follow lung nodules should use a lowradiation technique Techniques to reduce radiation dose are important, given the frequency with which follow-up CT examinations are performed Table 4: Summary of management pathway for SPNs by ACCP guideline [6] Risk for lung cancer Probability of malignancy Size (mm) No risk With risk Low (< 5%) Low or moderate (5 - 65%) High (> 65%) ≤4 No follow-up CT surveillance* - - - >4-≤8 CT surveillance* CT surveillance* - - - >8 - - CT surveillance* PET/CT and optional biopsy/resection Staging for treatment (*: Timing and term of CT surveillance depend on nodule size and appearance; ACCP: American College of Clinical Pharmacy) 158 Journal of military pharmaco-medicine no7-2019 Table 5: Summary of management pathway for single SPNs by Fleischner Society guideline 2017 [5] Risk for lung cancer Size (volume) < mm (< 100 mm ) - mm (100 - 250 mm ) > mm (> 250 mm ) Low risk (< 5%) High risk (≥ 5%) No follow-up Optional CT* surveillance CT surveillance* CT surveillance* with optional PET/CT, biopsy and/or resection (*: Timing and term of CT surveillance depend on nodule size and appearance) National Comprehensive Cancer Network (NCCN) guideline proposes different cut-off for size, follow-up interval and surveillance term depending on the appearance of the nodule, e.g., solid, part-solid, or non-solid Follow-up methods proposed by the Fleischner Society (2017) vary depending on whether the nodule is solid or sub-solid American College of Clinical Pharmacy (ACCP) guidelines outline similar methodology; follow-up methods mainly depend on nodule appearance, nodule size, and risk or probability of malignancy [3] If the nodule appears highly suspicious for malignancy, non-surgical biopsy or surgical resection should be carried out Most guidelines recommend non-surgical biopsy or surgical resection when the nodule develops a solid component The BTS suggests resection in cases where the nodule grows more than mm in maximum diameter even if the nodule retains a pure ground glass appearance PET/CT: Studies have shown that the sensitivity and specificity of PET for the diagnosis of malignant lesions can reach 87% and 83%, respectively However, PET also has its shortcomings Firstly, PET is not sensitive for nodules smaller than - 10 mm in diameter For patients with in situ adenocarcinoma, carcinoids and mucinous adenocarcinoma, PET may provide a false negative result, and false positive findings may occur in patients who have inflammatory reactions (sarcoidosis or rheumatoid nodules) or in a status of infection (fungal or mycobacterial infections) [5, 6] * Liquid biopsy: Liquid biopsy, which analyzes biological fluids especially blood specimen to detect and quantify circulating cancer biomarkers, have been rapidly introduced and represents a promising potency in clinical practice of lung cancer diagnosis and prognosis Unlike conventional tissue biopsy, liquid biopsy is non-invasive, safe, simple in procedure, and is not influenced by manipulators’ skills Notably, some circulating cancer biomarkers are already detectable in disease with low-burden, making liquid biopsy feasible in detecting early stage lung cancer [7, 8] Currently, varieties of circulating cancer biomarkers are available for liquid biopsy including tumor-associated antigens (TAAs), tumor-associated autoantibodies (TAAbs), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA), 159 Journal of military pharmaco-medicine no7-2019 exosomes and so on TAA markers detectable in serum like carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, CA199, neuron specific enolase (NSE), cytokeratin 19 fragment 21-1 (Cyfra 21-1) and squamous cell carcinoma (SCC) are hard to be used in detection of early lung cancer with poor sensitivity and specificity However, serum TAAbs, autoantibodies against overexpressed, mutated, misfolded, or aberrant autologous cellular antigens, may be associated with unique advantages in identifying individuals with early lung cancer That has been theoretically supported for reasons, which include: immuno-surveillance occurs in the early phase of cancer immuno-editing process and autoantibodies may be detectable in early stage of lung cancer; TAAbs can be present at high titers even tumor mass is low and are stable in blood CTCs are cancer cells directly shed off from primary tumor sites or metastatic sites and float in the circulation, which can be isolated as either single cells or clusters Ct-DNA is cell-free fragments of DNA shed into the bloodstream by tumor cells undergoing necrosis, apoptotic or active secretion events It is tumor specific and provides molecular clues about fragmented DNAs of tumor cells and their specific mutations Quantitative and qualitative analysis respectively on the amount and biological characteristics of ct-DNA provide real-time evaluations for diagnostic and prognostic assessments There is some other source of liquid biopsy-based biomarkers can be considered for early detection of lung cancer likes exosomes, MiRNAs and so on [7] 160 * Bronchoscopy: Development of technologies like virtual bronchoscopy (VB), electromagnetic navigation bronchoscopy (ENB), ultra-miniature (UM) radial probe EBUS (RP-EBUS) and ultrathin bronchoscopes has been a boon for bronchoscopists [9] - Traditional flexible bronchoscopy: Many studies have proved that this method has a low sensitivity of the lesion with the size less than cm, especially when the lesion is peripheral [9] - Virtual bronchoscopy and virtual bronchoscopy navigation: VB utilizes noncontrast CT of the chest to generate three-dimensional virtual image of the airways, which closely mimics the actual airways As selection of endobronchial pathway to the lesion can be a potential major source of error in reaching a peripheral lesion VB guidance can be very useful in selecting the appropriate airway Virtual bronchoscopic navigation (VBN) involves navigation to the peripheral lesion-using pathway based on airways leading to lesion planned using VB and simultaneous aligning and superimposition of virtual views on the actual bronchoscopic views [9] - Ultrathin bronchoscopy: Small bronchoscopes with an outer diameter of 2.8 - 3.5 mm are considered ultrathin although a formal definition doesn’t exist The small size of ultrathin bronchoscopes allows better maneuverability and they can visualize deeper into the tracheobronchial tree and can reach up to the - generation bronchi The ultrathin bronchoscopes are usually used with image guidance technology to reach close to the peripheral lesions [9] Journal of military pharmaco-medicine no7-2019 - Radial probe EBUS: The UM RPEBUS has a 20 MHz transducer at the tip which rotates 360° perpendicular to the direction of insertion and obtains real-time high-resolution images of the structures surrounding the airways The RP-EBUS can be inserted directly through the working channel of bronchoscopes or can be used with a guide system or through extended working channel (EWC) of electromagnetic navigation systems into the target bronchus to confirm appropriate localization of the area of interest Once the lesion is confirmed, the guide system is fixed in place and RP-EBUS is removed and various sampling instruments can be advanced through the guide system to sample the lesion Based on systemic reviews and meta-analysis, the overall sensitivity of RP-EBUS for diagnosis of peripheral lesions is around 70% although there is considerable heterogeneity in nodule characteristics and variable use of additional image guiding technology in included studies Major limitation of the technique is operator dependence [9] Electromagnetic navigation bronchoscopy: The ENB system works similar to the global positioning system (GPS) of the vehicles Like VB, the ENB technology requires thin-section CT to create a virtual bronchial tree This CT is performed prior to the procedure The lesion is reviewed in the axial, sagittal, and coronal planes and marked as the target Endobronchial pathways to the lesion are planned and marked using the virtual airways Many of the studies of ENB are small non-randomized single center studies with yield diagnostic yields ranging from 63% to 85% Significant factors associated with higher sensitivity were larger nodule size, presence of bronchus sign, nodule visualization with RP-EBUS and so on [9] * CT-guided biopsy (FNAB): fine-needle aspiration FNAB is a common method for lung tissue biopsies in clinical settings, particularly for SPNs located close to the chest wall The diagnostic accuracy mainly depends on an operator’s positioning and puncturing skills, in addition to the pathology technical level that may have a certain impact on the results With the established role of CT screening for lung cancer, and the broad application of high-resolution CT, the SPN are increasingly detected In recent years, an important type of pulmonary nodules has gradually increased, namely the subcentimeter nodules, which refer to those with a diameter < mm Although most SPN is benign, the pathology of the nodule is crucial to a patient with a history of cancer even if the SPN is small and peripheral FNAB is a minimally invasive diagnostic method, with a high positive diagnostic rate, less injury and low cost; so, it has been widely used in the routine diagnosis of SPN Diagnosis by FNAB on small nodules has the following features: - Wide adaptation range: Except for central type lesions, the diagnostic rate of bronchoscopy on the peripheral type and diffuse lesions is little while FNAB can be applied both in central type lesions or peripheral type and diffuse lesions, as long as there is no apparent adhesion in blood vessels - FNAB has a high accuracy: For lesions about 0.5 - cm, it can also successfully conduct biopsy under CT guidance 161 Journal of military pharmaco-medicine no7-2019 - High diagnostic accuracy: FNAB is a well-established, useful procedure However, the diagnostic accuracy of FNAB depends on the size and location of the lesion, as well as the guidance technique, and decreases from over 90% to 25% when the malignant nodule is small (< cm), and to 70% when the lesion is benign - High safety: Although FNAB is a safe and reliable examination method, it is still a traumatic investigation, so there are still some complications The main complications of FNAB mainly include pneumothorax and haemorrhage According to literature reports, the incidence of pneumothorax is about 10 - 40% while the incidence of pulmonary injury is about 26 - 33% [10] * Surgery: In the case of a high probability of malignant pulmonary nodules (> 60 - 70%), video-assisted thoracoscopic surgery (VATS) is the recommended strategy, for it satisfies the needs of both diagnosis and further treatment With a benign result from intraoperative frozen pathology, only wedge resection will be needed For malignant pathological findings, surgical resection should be selected in combination with systematic lymph node dissection [10] CONCLUSSIONS The management of SPNs involves both clinical and paraclinical assessment including risk assessment, morphology and histopathology of the nodule To assess each characteristic, doctors should apply different methods, with their own advantages and disadvantages Full use 162 of newer techniques should play an important role in diagnosis and management of SPNs REFERENCES Zhou Z, Zhan P, Jin J et al The imaging of small pulmonary nodules Translational Lung Cancer Research 2017, (1), pp.62-67 Kikano G.E, Fabien A, Schilz R Evaluation of the solitary pulmonary nodule American Family Physician 2015, 92 (12), pp.1084-1092 NCCN Lung Cancer Screening Panel Members Lung cancer screening, Version 3.2018 Journal of the National Comprehensive Cancer Network 2018, 16 (4), pp.412-441 Gould M.K, Donigton J, Lynch W.R et al Evaluation of individuals with pulmonary nodules: When is it lung cancer? Chest 2013, 143 (5), pp.93-120 MacMahon H, Naidich D.P, Goo J.M et al Guidelines for management of incidental pulmonary nodules detected on CT images: From the Fleischner Society Radiology 2017, 284 (1) Ito M, Myiata Y, Okada M Management pathways for solitary pulmonary nodules Journal of Thoracic Disease 2018, 10 (7), pp.860-866 Liang W, Zhao Y, Hoang W Liquid biopsy for early stage lung cancer Journal of Thoracic Disease 2018, 10 (7), pp.876-881 Castro-Giner F, Gkoutela S, Donato C et al Cancer diagnosis using a liquid biopsy: Challenges and expections Diagnostics (Basel) 2018, (2), p.31 Dhillon S.S and Harris K Bronchoscopy for the diagnosis of peripheral lung lesions Journal of Thoracic Disease 2017, (10), pp.1047-1058 10 Xu C, Hao K, Song Y et al Early diagnosis of solitary pulmonary nodules Journal of Thoracic Disease 2013, (6), pp.830-840 ... advantages and disadvantages Full use 162 of newer techniques should play an important role in diagnosis and management of SPNs REFERENCES Zhou Z, Zhan P, Jin J et al The imaging of small pulmonary. .. lesion is reviewed in the axial, sagittal, and coronal planes and marked as the target Endobronchial pathways to the lesion are planned and marked using the virtual airways Many of the studies of ENB... diagnosis and management Diagnosis of SPNs * Characteristics of risk factors: The probability of malignancy can be assessed clinically or by quantitative predictive models as falling into of risk categories: