Incidental Pulmonary Nodules – What Do We Know in 2022

Lung cancer (LC) claims the lives of almost 400,000 people in Europe alone each year [1], and most patients to date still get diagnosed at an advanced stage with very low 5-year overall survival rates of less than 10% [2‒4]. This is particularly tragic as screening with low-dose computed tomography (CT) in a clearly defined high-risk population has demonstrated survival benefit already in 2011 in the National Lung Screening Trial (NLST) [5‒7] which was confirmed later in several randomized controlled trials in Europe [8‒13]. Screening of high-risk individuals thus has the potential to lead to a stage shift and to significantly increase 5-year overall survival rates within the next few years. However, as the experience from USA shows, it seems difficult to successfully implement a national screening program, with currently only less than 10% of individuals at risk making use of the offer [14‒16]. Similar challenges can be expected in other countries; therefore, it might take many years to see a stage shift happening, with improved survival rates in cancer registries as a result.

A second, even larger opportunity to achieve the needed stage shift is through the increasing number of incidentally detected lung nodules which must be clearly distinguished from those detected by screening. Incidental pulmonary nodules (IPNs) are one of the commonest abnormal findings in radiology, as they can occur on every CT scan that includes the lungs or parts of them. Since imaging of the chest is increasingly used in various indications [17‒24], detection of IPNs will steadily increase [19, 21, 25].

Although only a small number of IPNs correspond to early-stage LC, it is critical to find and select the malignant ones from the crowd [19, 21, 26, 27]. Accurate assessment and appropriate subsequent follow-up of IPNs might be at least as crucial as screening programs in improving LC mortality [28‒30].

This is particularly important, since IPNs often occur in individuals who generally do not match the population who would be eligible for LC screening due to their very heterogeneous sociodemographic and medical characteristics [19, 31] and therefore defining a separate group, different from the LC screening population. The major problem, however, is that in the USA, for example, estimated 1.1 million IPNs per year seem to be not appropriately followed up and worked up as shown by several analyses of US health data [19, 25, 32].

In recent years, specially designed IPN management programs have been developed, mainly in the USA, to improve the work-up process [28‒30, 33]. Implementation of such IPN management programs has shown that this can lead to a higher rate of early detected LC, especially in subjects who would not be eligible for LC screening [28‒30, 34, 35]. Therefore, a combined approach including both LC screening in high-risk individuals and proper follow-up programs for those with IPN seems to be a key factor for improving LC mortality covering a large population of potentially affected individuals.

So far, little to no data have been published regarding the real-world situation of IPNs in European countries. The reality of IPN management is a “black box,” and we can only speculate how many IPNs may be overlooked in Europe.

Given the dynamic in this field, and the high number of publications on this topic in recent years, this article reviews the current state of knowledge, summarizes recent guidelines, and gives an overview where the field is heading, based on latest global developments. The current status and outlook are intended to provide awareness and guidance for physicians in IPN management. Additionally, shortcomings in current management strategies and future areas of research are also discussed.

IPNs are nodules that were not explicitly looked for in a screening program but were found incidentally in CT scans which were performed for an unrelated reason such as trauma, pulmonary diseases, cardiac and mediastinal pathologies, or currently, the SARS-CoV-2 pneumonia [17‒24]. According to the glossary of term from chest imaging proposed by the Fleischner Society, an IPN is a collective term for space claims of the lungs >3 mm and ≤3 cm in diameter without assignment of a specific dignity [36]. IPNs can occur as single or multiple event [27, 37]. On the radiologic image, IPNs can be seen as more rounded structures having a sharp or indistinct border to the surrounding tissue [37]. They can be in contact with the pleura, but usually they are surrounded completely by aerated lung on CT scan [37]. In accordance with their radio-morphology, IPNs are classified as solid or subsolid nodules, whereby the subsolid nodules are further differentiated into pure ground-glass (pGG) nodules and mixed-solid (part-solid) nodules [31, 37, 38]. An overview about the classification is given in Figure 1.

Solid IPNs are the most common kinds of nodules. An IPN is classified as solid if its solid fraction is at least 80%. On CT images, they may completely obscure bronchial and vascular structures pervading the IPNs (shown in Fig. 1) [39]. pGG nodules represent subsolid nodules with increased lung attenuation so that parenchymal structures are visible throughout them (shown in Fig. 1) [39, 40]. In contrast to that, part-solid nodules consist of ground-glass and solid components, and consequently, they do not completely obscure the underlying lung architecture (shown in Fig. 1) [39‒41]. pGG nodules <6 mm have a high prevalence in the population. They are often transient and usually associated with infection or hemorrhage, while persistent pGG nodules are suggested to have a higher risk of malignancy [42] as they can represent a premalignant precursor/progenitor of an adenocarcinoma [39].

Early reviews suggested that in the year 2000 pulmonary nodules were detected in approximately 150,000 Americans each year [43, 44]. In 2015, Gould et al. [19] retrospectively analyzed health data from US patients. In this analysis, the frequency of nodule detection raised from 24% to 31% for all scans performed between 2006 and 2012 [19] and was linked to the enhanced performance of chest CT scans during that time frame (from 1.3% to 1.9%) [19]. Results corresponded to an increase of the annual rate of nodule identification from 3.9 to 6.6 per 1,000 person-years [19]. In Europe, similar results have been observed. A study including patients from 5 regions of northeastern France whose data were analyzed between 2002 and 2005 revealed an incidence up to 12.6/100,000 person-years [45]. Consistent with Gould et al. [19], the incidence rate increased in the French study population (age-standardized rate men: from 16.4 to 17.7 per 100,000 person-years; women: from 4.9 to 8.2 per 100,000 person-years) [45]. In another European study, analyzing data from two large Dutch hospitals, the percentage of patients with an incidentally detected pulmonary nodule increased from 33% to 50% in 10 years corresponding to the augmented rate of chest CTs performed per year (plus 64% in 10 years) [46]. In China, a retrospective study including 64,168 patients undergoing chest CT revealed a significant portion of patients (59%) with at least one noncalcified IPN [47]. Although the proportion of patients with IPNs varies between 10% and 59% in the literature [25, 47], it is evident that IPNs are very common in the population, even in those subjects, who are not eligible for LC screening [19, 28]. Due to the steadily increasing use of abdominal and thoracic CTs [48], extrapolation of the data suggests that in 2015 ∼1.6 million IPNs were detected by CT scans in 1 year in the entire US population [19].

In recent years, several strategies have been published that address IPNs as well as screening-detected nodules. The Fleischner Society [31] is one of the few guidelines that refer only to IPNs, whereas guidelines from other societies such as the British Thoracic Society (BTS) [37], the American College of Chest Physicians (ACCP) [49], and the National Comprehensive Cancer Network (NCCN) [50] include recommendations for both, incidentally and screening-detected nodules. All mentioned guidelines [31, 37, 49, 50] consider nodule characteristics found on actual and previous imaging scans and individual clinical risk factors for LC development to evaluate the probability of malignancy and to determine the most appropriate management strategy. In addition, there are local national guidelines, such as the newly revised 2022 German S3 guideline [51], in which a chapter with recommendations on IPNs has been newly added. These local guidelines are based on literature review, evidence assessment, and derived recommendations, most of which are consistent with the Fleischner Society and BTS guidelines. Differences between these two guidelines are shown in Table 1.

The American College of Radiology developed the Lung CT Screening Reporting & Data System (Lung-RADS) [52] which has become commonly used in screening practice and differs from the approach for incidental nodules. Thus, it is not mentioned in detail here.

Estimating the probability of malignancy is the major task, as this is the basis for deciding on subsequent management. Morphology, location, size, multiplicity, and growth rate of the identified nodule(s); the assessment of present pulmonary diseases (e.g., emphysema and fibrosis); assessment of patient demographics (including age, sex, race, family history); and documentation of inhalation of toxic compounds (e.g., tobacco smoke, fumes, or dust) must be considered for this purpose [19, 31, 37].

In general, nodules with smooth border, total or partly calcification, solid density, very fast (<1 month) or rather long (>1 year) doubling time, and a size ≤6 mm in diameter are suggested to be benign [19, 53, 54]. Fatty degeneration and calcification are further suspected as benign characteristics in pulmonary nodules. However, the risk of malignancy appears to raise with increasing diameter [27, 55]. Solid nodules <6 mm in diameter are supposed to become rarely malign in contrast to solid nodules ≥6 mm in diameter [27, 31, 39, 56, 57]. Location also plays a role in risk assessment. Upper lobe location is associated with a higher risk. Small solid nodules in a perifissural or subpleural location often represent intrapulmonary lymph nodes and have a low risk of malignancy [58]. Regarding subsolid nodules, many are associated with benign conditions such as focal interstitial fibrosis, eosinophilic pneumonia, thoracic endometriosis, and focal hemorrhage [59]. However, pGG nodules with a larger size (diameter >10 mm) or bubbly transparency should receive certain awareness as they have a higher probability of developing malignancy [60]. Additionally, numerous studies have shown that pGG nodules ≥6 mm need in average 3–4 years to establish growth or to be diagnosed as developing invasive carcinoma showing that even smaller pGG nodules may become malign over time [61‒63]. Part-solid nodules are also known to have a high likelihood of malignancy as shown in the Early Lung Cancer Action Project (ELCAP) study where a malignancy rate for 63% was observed for part-solid nodules [42]. However, in general, the malignancy rates of subsolid nodules are markedly higher than that of solid nodules (34% vs. 7%) [42].

Currently, the following individual risk factors in patients with newly identified lung nodules have been identified (shown in Table 2) [31, 64] which are almost congruent with the risk factors postulated by others [19, 27, 31, 37, 64, 65]. Based on these independent risk factors (shown in Table 2), a pre-test probability of malignancy of IPN can be calculated [37, 49]. Additionally, the BTS guideline endorses [37] the use of the prediction models from Herder et al. [66] and Brock model [27] as additional decision aid for nodule judgment in patients with newly identified lung nodules. In the Brock model [27], for example, the individual risk of malignant disease is estimated as a percentage. Based on this model, a risk profile of more or less than 10% is the cut-off between noninvasive CT follow-up and invasive diagnostics. However, the application of these models to clinical practice should take into account the population characteristics from which each model was derived. As all risk models have been validated in LC screening populations, they may not be appropriate for every individual patient with IPNs [27, 37].

Imaging standards for the optimal assessment and follow-up of nodules have been defined and described by scientific societies and are included in current guidelines [31, 37, 51]. It is important to emphasize, that all follow-up examinations should be performed in low-radiation technique, and that thin slice reconstruction should be used (≤1.5 mm, ideally 1.0 mm). Another important aspect is the use of three-dimensional measurements (volumetry), instead of diameter. The measurement of the maximal transversal diameter often leads to an overestimation of nodule size because lung nodules usually do not have a perfectly spherical shape which then results in an increased number of false-positive cases. The NELSON trial has demonstrated the advantage of using volume change to measure tumor growth with lower false-positive scan rates (e.g., 1.2% vs. 23.3% in the NLST) than in other trials resulting in less invasive diagnostic procedures [5, 8]. Another positive aspect of volumetry is a faster detection of growth which is not possible using the diameter measurement since it is difficult to detect a critical diameter growth of 25% before the IPN has doubled its volume [67].

Although currently available guidelines from the major medical societies provide recommendations for management of pulmonary nodules, several studies suggested that not all stakeholders are familiar with them and/or used them consistently at their work [68‒73], even among radiologists the level of awareness and utilization of the guidelines varies considerably between countries from 27% to 61% [70‒73]. Among hospitalists practicing internal medicine, up to 42% are not familiar with the guidelines from the Fleischner Society, although IPNs are frequently seen in their clinical routine (at least one IPN/6 months) [73]. The wide disparities in adherence to the guidelines among both radiologists and other involved physicians such as pulmonologists, internists, and general practitioners indicate that there is still room for refinement. A significant improvement in guideline compliance was already seen with simple approaches such as printing the Fleischner Society guidelines on small cards and attaching them to workstations where radiologists or other physicians interpret CT examinations [74] or adding the Fleischner recommendations to radiological report templates [25, 75‒77] or to chest CT reports to encourage their usage by radiologists and general practitioners [78].

Although every year, hundreds of thousands of IPNs are detected on CT scans, follow-up appears to be insufficient in most of the newly detected nodules since rates of follow-up care ranged from 29% to 39% [25, 32, 79] raising the question of why approximately 2 out of 3 patients with IPNs do not seem to receive a proper radiological and clinical follow-up [25]. These results are rather interesting as majority of the radiological reports (up to 68%) had recommended a follow-up of the pulmonary nodules [25] indicating a significant lack of adequate nodule work-up in many patients with potential early-stage cancer. Several pitfalls are described in the literature that may be responsible for inadequate management of IPNs [25, 33, 79‒81] showing that, even if the radiologist initiates the IPN management process by documenting them in the radiology report, he is not solely responsible that IPNs are often neglected. Different health care providers and patients also represent important factors in the success of IPN management. Figure 2 shows exemplary a patient journey from the onset of pulmonary nodule discovery with potential pitfalls encountered in the evaluation of IPNs, highlighting the challenges in clinical practice and the high demands placed on radiologists.

In recent years, several approaches were developed to address current shortcomings of nodule management. One approach is the modification of the radiological report template to ensure concise and guideline compliant description of incidentally detected nodules by the radiologist (see section What Do We Know about Guideline Adherence?) [25, 76, 77]. Aase et al. [77] demonstrated that the inclusion of six key nodule descriptors (average diameter, location, density, suspicious features of the dominant nodule, total number of nodules, and risk stratification) in the radiological report template significantly increased the number of reports including all descriptors from 12% to 47% (p < 0.001).

Other approaches comprise computerized closed-loop communication and multistage tracking systems, such as Alert Notification of Critical Results (ANCR) [83, 83] and Result Alert and Development of Automated Resolution (RADAR) [84], to control completeness of follow-up imaging, and to provide reminders to patients and/or physicians if the recommended follow-up has not been performed [82, 85‒89]. The ANCR system includes creation, communication, and acknowledgment of alerts as well as their management including reminder and escalation. Responses are created automatically by the system and communicated via paging or secure mails to involved parties [83, 90]. Several studies demonstrated that ANCR usage reduced medical errors, increased the adherence to institutional guidelines for communication of critical results (improvement from 91% to 95%, p < 0.0001), and reduced workflow interruptions: all properties that improve the quality of patients’ care [83, 90].

The RADAR system is another example of how closed-loop system integration can manage recommendations in accordance with the Fleischner Society guidelines [84, 85]. RADAR is embeddable in the picture archiving and communication system [91] generally used by radiologists. A retrospective analysis in a tertiary academic center with more than 600,000 radiology examinations annually revealed that in all RADAR alerts, imaging modality and follow-up time frame were stated whereas in non-RADAR alerts, only 71% of them had a complete documentation (p value <0.001) [84]. Additionally, after implementation of RADAR, the timely follow-up rate was increased (from 65% to 84%, p = 0.0001) and the agreement between primary care provider and radiologists regarding IPN management plan was high (87%) [85].

Another tracking system developed by Dyer et al. [88] is coupled with a computerized registry using tracker phrases for nodule description which then automatically generate follow-up recommendations for the radiological report in accordance with the Fleischner Society guidelines. Besides the autonomous calculation of patients’ LC risk, the system is also able to check whether the recommended follow-up has taken place and issues appropriate reminders if examinations are still pending [88]. The implementation of the system increased the timely follow-up rate from 46% before to 55% after implementation of the system [88].

Over the past few years, artificial intelligence (AI) has been increasingly used to aid automatic detection and characterization of lung nodules [92, 93]. In addition, the malignancy of nodules can also be assessed using nodule volumetry. Computer-aided detection has the potential to analyze nodule morphology and improve the workflow of follow-up assessment [93].

Thus, the use of AI in diagnostic imaging relieves the burden on radiologists and is associated with an increased accuracy of IPN assessment which in turn enables a more frequent detection of early-stage LC, possibly resulting in a stage shift in LC diagnosis [93, 94]. Recent evidence has demonstrated that deep learning algorithms have similar model performance to radiologists in predicting LC risk to even better performance especially for less skilled readers [95‒98].

Although there are already commercially available AI software solutions on the market that have already received FDA clearance and CE mark [99], AI solutions have not yet found their way into everyday clinical practice. Most important is the full integration of these tools into the clinical radiology workflow, and it is precisely this factor that is one of the main reasons for the lack of acceptance of already available computer-aided detection tools [100]. However, we expect that the coming years will bring significant progress and that these technologies will then become the standard of care and revolutionize radiologists' workflows.

While in European countries, IPNs are usually managed by the respective specialty departments, specialized pulmonary nodule clinics have already been established in the USA providing work-up and treatment of lung nodules in an optimized surrounding [29]. Key factor in such nodule clinics is the so-called lung navigators who are responsible for the timely performance of designated procedures and patient support [29]. Pulmonary nodule management is a complex process often confusing affected patient. Lung navigators can effectively address this problem by educating patients and easing their transition from the multidisciplinary clinic to individual specialists, which helps prevent patients from getting lost in the complicated follow-up process. Further, consequent support by specialized nurses improves adherence to recommendations as there is a certain kind of guidance and control for the patients.

In addition to improving patient compliance with follow-up recommendations [28], the most important outcome achieved through the establishment of pulmonary nodule programs and specialized lung nodule clinics is the stage shift in LC detection [28‒30]. In one study, implementation of the nodule management program enabled that 33% of the patients with LC received an early-stage diagnosis (IA or IB) [30]. In another lung nodule program, the percentage of patients with early-stage LC at time of detection increased from 23% to 38% within 2 years [28]. First results of a specialized lung nodule clinic showed that 94% of the patients had stage I or stage II at the time of diagnosis enabling a promising prognosis [29].

Lung nodule programs, patient tracking software, AI, and communication software to engage referring clinicians are efficient and effective tools to ensure planning, organization, and control of adequate follow-up of IPNs in clinical practice and significantly improve patient care, but it has to be considered that such approaches require well-organized teamwork [28‒30, 33‒35, 47, 81, 82, 86‒88, 90‒97]. However, outcomes of several studies showed that utilization of such tools is first step to achieve a true stage shift in LC diagnosis [28‒30].

To improve LC mortality, it is urgently needed to achieve a stage shift toward earlier disease. Two parallel approaches are necessary to drive this stage shift: first, implementation of national LC screening programs in high-risk populations, and second, appropriate follow-up and management of the increasing number of incidentally detected nodules. Regarding IPNs, data suggest that a high number of patients are lost to follow-up and, thus, miss the chance for early diagnosis in cases where the nodule is malignant. Reasons for insufficient follow-up are numerous. Recent experience from USA has demonstrated that follow-up rates can be increased by structured nodule management programs, which in some cases has resulted in a stage shift. Critical factors for a successful and timely follow-up include the use of AI software for nodule evaluation, comprehensive reporting of the findings, effective communication between involved parties including patients’ awareness to the findings, establishment of patient tracking systems, clear responsibilities for scheduling and managing the follow-up, e.g., through a lung nodule navigator or nurse. Additionally, comprehensive education, raising awareness, and adherence to guidelines on the part of the physicians and persons involved such as general practitioners, radiologists, thoracic surgeons, oncologists, and pulmonologists are essential to ensure adequate IPN management.

In the future, in addition to the introduction of LC screening programs, the focus should continue to be on the development and optimization of specific IPN management programs for incidentally detected lung nodules, especially in those countries where little has been initiated to this end (e.g., Europe). The two approaches work complementarily, and together, they will reduce the disparities that exist in access to LC screening programs by enabling different at-risk populations to participate in LC screening and appropriate treatment. As a result, it will be possible to increasingly diagnose LC at early stages and, finally, to improve survival rates from this devastating disease.

The authors would like to thank Dr. Katharina Bakhaus, Alcedis GmbH, Giessen, Germany, for medical writing assistance.

Gerald Schmid-Bindert and Joana Fink are employees of AstraZeneca. However, there are no conflicts of interests in this context, since this work is part of the Lung Ambition Alliance. All other authors have no conflicts of interest to declare.

AstraZeneca is supporting this article in the context of the Lung Ambition Alliance (LAA) initiative, where AZ and IASLC are partnering with the goal to support projects that have the potential to improve lung cancer 5-year-survival rates, independent of drug development. The medical writing assistance for this review was therefore funded by AstraZeneca, Hamburg, Germany.

Gerald Schmid-Bindert, Jens Vogel-Claussen, Sylvia Gütz, Joana Fink, Hans Hoffmann, Martin Eichhorn, and Felix J.F. Herth were involved in the conceptualization of the manuscript. Gerald Schmid-Bindert and Joana Fink prepared the original draft preparation. Gerald Schmid-Bindert, Jens Vogel-Claussen, Sylvia Gütz, Joana Fink, Hans Hoffmann, Martin Eichhorn, and Felix J.F. Herth were involved in the review, writing, and editing of the manuscript. All authors have read and agreed to the final version of this review article.