Introduction
Lung cancer is a serious medical, social, and economic problem. Despite the advances in the treatment of other neoplasms, achieved within recent years, the 5-year survival rate of lung cancer patients remains very low. Globally, approximately 1,448,000 individuals develop lung cancer each year. In developed countries, lung cancer is the third most frequent cause of death after coronary artery disease and stroke [1]. In the USA, lung cancer is the second most frequently developed malignant neoplasm after prostate cancer in men and breast cancer in women. In both sexes, lung cancer is responsible for the largest number of deaths resulting from neoplastic disease: in men, it surpasses the next 4 most frequent neoplasms counted together; in women, it results in almost twice as many deaths as breast cancer [2]. According to global statistics, the incidence of lung cancer and the number of deaths caused by it in Poland are higher than in other highly and moderately developed countries. In 2008, the estimated number of new cases for both sexes in Poland was 71.21 per 100,000, placing our country in third place, after Hungary and Armenia [3].
Screening examinations for lung cancer have been a matter of controversy for years. It has been proven that screening in the form of cytological sputum analysis and chest X-ray examinations falls short of its goals [4]. In 2011, the results of the multicenter, randomized study “National Lung Screening Trial” were published: the study demonstrated a 20% mortality reduction in the study group examined with low-dose computed tomography (LDCT) in comparison to the control group assessed with traditional X-ray examinations [5]. Low-dose computed tomography screening has been recommended by the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology, and the American Association for Thoracic Surgery [6, 7]. The U.S. Preventive Services Task Force also published its positive recommendation concerning lung cancer screening in 2013 [8].
Performing yearly low-dose computed tomography examinations is recommended in individuals at a high risk of lung cancer:
•
aged 55-74 years,
•
active smokers and ex-smokers who ceased smoking ≤ 15 years ago,
•
who have smoked 30 pack-years or more [6-8].
Apart from reducing lung cancer mortality rates in individuals undergoing yearly low-dose computed tomography examinations, another benefit of the screening procedure is that it provides an opportunity for smoking cessation interventions [6]. The combination of screening and smoking cessation interventions is also considered to be a cost-effective method [9]. On the other hand, the relatively large number of false positives, the potentially unnecessary invasive diagnostics in the case of benign pulmonary changes, and the reduced quality of life and increased anxiety of patients, associated with finding lung tumors, constitute the drawbacks of screening examinations [6, 10].
With the popularization of computed tomography, finding new lung tumors constitutes an increasingly frequent clinical problem despite the availability of many advanced examination methods and international guidelines. When selecting a diagnostic method, physicians often face various alternative courses of action. Should they diagnose or observe? When should a lung tumor biopsy or a positron emission tomography (PET) scan be conducted? Or should the patient be referred for surgical removal of the lesion immediately?
The year 2013 saw the publication of updated guidelines for lung cancer management: “Evaluation of individuals with pulmonary nodules: when is it lung cancer?” by the ACCP [11] and “Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the fleischner society” [12]. The focus of the present review is the course of action after revealing a new round pulmonary shadow up to 30 mm in diameter.
Imaging diagnostics
Radiological examination of the chest (X-ray examination)
Chest X-ray is most commonly the first examination performed when diagnosing lung cancer. The method is essential in diagnosing many disorders of the chest, but its efficacy as a screening examination is unconfirmed. Lung tumors revealed by it require further diagnostics – computed tomography. The role of X-ray examinations in lung cancer diagnostics is currently small, as it is being replaced by LDCT.
Computed tomography of the chest (CT examination)
Computed tomography examination enables the precise assessment of the size, shape, margins, and density of lung tumors. It also facilitates the evaluation of lymph nodes, additional pulmonary changes, as well as chest wall and mediastinal infiltration. Many tumor features allow the physician to estimate the risk of tumor malignancy. Malignant tumor features include spiculated outlines, post-contrast enhancement of more than 15 Hounsfield units (HU), and vascular convergence [13]. Tumor cavitation suggests with high probability that the tumor is malignant, especially if the cavity is irregular and thick-walled [14]. The presence of spiculated outlines increases the risk of a malignant process five-fold, an image of pleural retraction increases it two-fold, and the so-called vessel sign increases it by 70% [14]. Conversely, the risk that the tumor is malignant is 30% lower if an air bronchogram is visible, and five times lower if the tumor’s outlines are smooth [14].
Computed tomography reveals a tumor – what next?
The first step consists in determining whether the change is a neoplasm. The ACCP recommends estimating the probability of a neoplastic change before selecting diagnostic methods in patients who can potentially be qualified for surgical treatment. Subjective clinical assessment should be performed along with, when possible, a quantitative evaluation using validated methods [15-18]. Table I presents the methods of clinically assessing the probability of lesion malignancy [11].
Quantitative assessment of the probability of tumor malignancy
Several quantitative methods of assessing the probability of pulmonary lesion malignancy have been designed [16-22]. These models are based on basic probability theory and Bayes’ theorem. Table II presents the variables employed by the models.
Volumetric assessment
Computed tomography examinations, especially screening examinations employing LDCT, often reveal nodules in the lung parenchyma [10, 23]. In order to reduce the percentage of false positives, a volumetric evaluation of pulmonary changes in ml or mm3 is used. Tumor doubling time is also assessed, in accordance with Schwartz’s theory of exponential neoplasm growth [24]. The Dutch-Belgian randomized NELSON study successfully employed a method of volumetric tumor growth evaluation. Tumor growth by 25% and tumor doubling time < 400 days were set as criteria for malignancy [25].
Managing solid lung tumors 8-30 mm in diameter
The physician should inform the patient about the health issue, present the alternative management methods – diagnostics, observation, and surgical removal – and explain the risk of complications. Figure 1 presents a scheme for managing new-found solid lung tumors.
As the diagram above indicates, there is a certain amount of freedom in deciding how to manage solid lung tumors larger than 8 mm in diameter. Intuitively, managing round lesions with smooth outlines found in young non-smokers should differ from the course of action taken if large spiculated lesions are found in regular smokers. The literature features several studies presenting validated models of quantitatively evaluating the probability of malignancy in solid lung nodules. The range of quantitative methods for assessing the probability of lung lesion malignancy may additionally facilitate the selection of a proper course of action [15, 16, 18]. Communication with the patient, constituting one of the most important elements, should not be neglected; the patient should be presented with the available options in a straightforward manner. The decision concerning the management course should be taken by an informed patient.
Monitoring
Monitoring nodules by control CT examinations is one of the least invasive options that can be suggested. This course of action may be applied in the case of a fully informed patient, especially if the probability that the lesion is malignant is very low (< 5%). This option may also be selected if the risk is moderate (5-65%), PET/CT scans reveal low metabolic levels, or contrast-enhanced CT does not reveal an enhancement of more than 15 HU. It may also be chosen if the lung tumor biopsy is negative and PET/CT shows low metabolic levels.
Monitoring should be conducted based on LDCT without contrast after 3-6 months, and, subsequently, after 9-12 and 18-24 months. Solid lung tumors whose dimensions do not increase within 2 years of observation do not require further examinations. However, if the dimensions of the pulmonary nodules increase during the follow-up period, biopsy or excision is recommended. If the nodule’s size is reduced, observation should be continued until complete lesion regression or up to 2 years [11].
Positron emission tomography/computed tomography examination
In patients with moderate risk of lung cancer development (5-65%), PET examinations are recommended in order to evaluate the metabolic activity of the tumor. If the risk is high (> 65%), PET examination is not required for the assessment of tumor metabolism. In this situation, PET may be indicated for staging the neoplasm [11].
Tumor biopsy under computed tomography control
Tumor biopsy should be performed in the following cases:
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if the results of the imaging examinations and the evaluation of the probability of malignancy are inconsistent;
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if the probability of malignancy is moderate (5-65%);
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if benign disease requiring specific treatment is suspected [11].
Surgical resection
Surgical excision is recommended if the tumor is proven to be malignant by transthoracic aspiration biopsy or if no such confirmation has been obtained, but:
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the clinical probability of a malignant lesion is high (> 65%),
•
the tumor shows high metabolic activity in PET/CT,
•
the cytological results from the biopsy raise suspicions of malignancy,
•
the fully informed patient demands a definitive diagnostic procedure.
When possible, it is recommended to use minimally invasive operative techniques and tools for perioperative tumor localization [11].
Managing solid tumors smaller than 8 mm in diameter in patients with a low risk of lung cancer
Nodules with diameters ≤ 4 mm do not have to be monitored, but the patient should be informed about the potential consequences. Nodules with diameters of 4-6 mm should be evaluated by control CT after 12 months; if their size does not change, they require no further monitoring. Nodules with diameters of 6-8 mm should undergo monitoring after 6-12 months and, if they do not increase, 18-24 months after the first examination. Patients with numerous nodular lung lesions should be monitored based on the diameter of the largest nodule. Nodules up to 8 mm in size should be monitored using low-dose computed tomography without contrast [11].
Managing solid tumors smaller than 8 mm in diameter in patients with an increased risk of lung cancer
Nodules with diameters ≤ 4 mm should be monitored with CT after 12 months; if their size does not change, they require no further monitoring. Nodules with diameters of 4-6 mm should be monitored after 6-12 months, and, if no increase is revealed, 18-24 months after the first examination. Nodules with diameters of 6-8 mm should be monitored after 6-12 months, and, if they do not increase, 18-24 months after the first examination. Patients with numerous nodular lung lesions should be monitored based on the diameter of the largest nodule. Nodules up to 8 mm in size should be monitored using low-dose computed tomography without contrast [11].
Managing pure ground-glass nodules
Individuals diagnosed with pure ground-glass nodules (GGNs) up to 5 mm in diameter do not require further surveillance. According to the Fleischner Society, pure GGNs > 5 mm should be followed up after 3 months in order to determine whether they have regressed; subsequently, they should be followed up yearly for at least 3 years [12]. According to the ACCP, pure ground-glass nodules with diameters exceeding 10 mm should be followed up after 3 months, and, if no regression is observed, they should undergo biopsy or surgical removal [11]. Table III presents the recommendations of the Fleischner Society with regard to pure GGNs [12].
Managing part-solid ground-glass nodules
Part-solid GGNs with diameters ≤ 8 mm should be monitored after 3, 12, and 24 months, and then yearly for a period of up to 3 years. It is recommended that the conducted control examinations do not involve the use of contrast and employ thin layer techniques. If part-solid and non-solid tumors are shown to grow, consolidate, or be potentially malignant during the observation, special evaluation is required, and surgical resection may be considered. In the case of part-solid tumors with diameters > 8 mm, CT monitoring is recommended after 3 months. If the lesion does not regress, biopsy and/or surgical excision should be considered. Ground-glass nodules that have changed their state from non-solid during the observation or have direct contact with the pleura deserve special attention, as the probability that the lesion is malignant is very high in such cases [12]. Positron emission tomography scans are not recommended for part-solid nodules in which the solid component is smaller than 8 mm. A non-diagnostic biopsy does not allow one to exclude tumor malignancy. During the biopsy, the use of a radioactive dye marker or wire can be considered in order to facilitate the performance of a surgical resection [11, 12].
Is a cytological diagnosis from lung tumor biopsy indispensable?
No
Fine-needle aspiration biopsy or core needle biopsy of lung tumor tissue is an invasive examination with some risk of complications. The most frequent ones include pneumothorax, bleeding, air embolism, and implantation of the tumor into the chest wall. Table IV presents an overview of the available reports concerning complications. The risk of death associated with biopsy complications remains below 1% [11]. Regardless of biopsy results, patients may be qualified for surgical treatment. Omitting biopsy may allow the patient to avoid potentially painful procedures burdened with some risk of complications. The ACCP recommends that qualifying the patient for a surgical procedure (wedge resection of the tumor with intraoperative assessment) can be considered if, according to clinical or quantitative evaluation, there is a high probability (above 65%) that the tumor is malignant.
Yes, biopsy is indicated in lung tumor diagnostics
Lung tumor biopsy can confirm the presence of a malignant lung tumor with significant probability – 70-90%. In 30% of patients, it can also confirm that the lesion is benign. Preoperative cytological diagnostics may help reduce the percentage of benign lung tumor resections, which is approximately 9-15% [26]. Preoperative neoplasm diagnostics may change the methods of managing the disease and result in reducing healthcare costs. It also allows patients to make more informed decisions [27]. In experienced centers, the success rate of performed biopsies, regardless of nodule size, is nearly 100%.
Conclusions
Cytological lung tumor diagnostics is helpful in making correct clinical decisions and reduces the risk of unnecessary interventions. Biopsy under CT control is a relatively safe and reliable diagnostic method. This minimally invasive procedure may help reduce the percentage of benign lung tumor resections and result in lowering healthcare costs.
Disclosure
Authors report report no conflict of interest.
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