In patients with non-small cell lung carcinoma (NSCLC), mediastinal staging is essential for determining both prognosis and optimal treatment. The initial study of the mediastinum is based on computed tomography (CT) and positron emission tomography (PET), both separately and in combination (PET/CT). However, imaging techniques have diagnostic limitations and in some cases a negative result may hide mediastinal nodal involvement. More specifically, 3 clinical situations have been associated with a high rate of false-negative PET results: tumors larger than 3 cm in diameter; N1 involvement in imaging tests; and centrally located tumors. For this reason, evidence-based clinical guidelines for presurgical mediastinal staging of NSCLC released by the European Society of Thoracic Surgeons (ESTS),1 the American College of Chest Physicians (ACCP),2 and the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR)3 recommend invasive mediastinal staging not only in patients with pathological mediastinal findings on CT and/or PET, but also in individuals with normal mediastinum in any of the 3 clinical situations described. While the measurement of tumors larger than 3 cm can be objective and is relatively easy to perform, the determination of centrally located tumors is very controversial as there is no uniform definition of central tumor location. The ESTS refers to “tumors located in the inner two thirds of the lung”, whereas the ACCP refers to “tumors located in the inner third of the hemithorax”, and SEPAR refers to “centrally located tumors, usually in contact with the mediastinum”. Moreover, other definitions of central location described in scientific studies (such as that of Gómez-Caro et al.)4 or in guidelines from other societies (for example, as an exclusion criterion for stereotactic radiation therapy)5 have only added to the confusion. This lack of uniformity leads to wide variability in clinical practice among professionals responsible for managing patients with NSCLC. In this regard, a survey of 218 thoracic surgeons and pulmonologists was recently conducted in the United States.6 The results showed that professionals responsible for the care of NSCLC patients used a wide range of criteria for defining central lesions. Given this lack of uniform criteria in the literature and among the different societies, the SEPAR Thoracic Oncology area identified a need for a cross-sectional study to assess the situation in Spain. The aim of our study, then, was to evaluate the degree of familiarity with various concepts related to central tumor location among professionals who treat NSCLC patients in Spain. More specifically, the aim was to evaluate: 1) uniformity in the definition of central tumor location; 2) uniformity in the classification of lesions that extend beyond dividing lines; and 3) respondents’ ability to delineate lesions in the absence of dividing lines.

A freely accessible questionnaire composed of multiple-choice questions, with or without chest CT images, was sent by e-mail to all members of the Thoracic Oncology area of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), the Spanish Society of Thoracic Surgery (SECT), the Spanish Lung Cancer Group (GECP), and the Spanish Society of Cardiothoracic Imaging (SEICAT).

A total of 430 respondents completed the questionnaire. The majority were aged 30–45 years (45.9%), were pulmonologists (53.5%), and were directly involved in the diagnosis of lung cancer (86.5%).

Ability to correctly classify a lesion in the absence of dividing lines

Most respondents (78.6%) were able to classify a central lesion in the absence of dividing lines (image 12), with no significant differences between specialties (Table 3). Similarly, age, sex, or direct involvement in the management of patients with lung cancer did not influence the answer to any of the questions.

Table 3.

Ability to correctly identify a central node in the absence of dividing lines (Figure 12). Most respondents can correctly identify a central lesion (green boxes) in the absence of the dividing lines. No significant differences were observed between groups.

NS/NA: Not sure/not answered.

aFisher’s exact test p = 0.18.

Our survey, conducted among more than 400 professionals involved in the diagnosis and treatment of lung cancer in Spain, shows that the definition of centrality most widely accepted by respondents is not included in any of the clinical guideline proposals. The results also reflect a significant lack of uniformity in the classification of central tumors, although respondents’ responses show distinct patterns: the preferred dividing lines are radial concentric lines arising from the hilum (B lines); the most widely accepted limit for centrality is the inner third; and in most cases it is agreed that a lesion that crosses a dividing line should be classified according to where most of its volume is located. It is also important to note that, despite the subjective nature of the current definitions, most survey respondents were able to properly define a central lesion in the absence of dividing lines.

The concept of centrally located tumors was introduced by Daly et al.7 in 1987. These authors reported that centrally located tumors, which they defined as lesions observed on flexible bronchoscopy or visualized in the inner third of the lung in the anterior-posterior projection of the chest X-ray, were more likely to have occult mediastinal nodal involvement on chest CT. In the 1990s, with the introduction of the first PET machines - with low image resolution - it was accepted that centrally located tumors could hide mediastinal lymphadenopathies located in their vicinity. This phenomenon was known as the hot-spot effect. In the 2000s, additional evidence that centrally located tumors are associated with a higher rate of false negatives in imaging tests has appeared and new definitions of central location have been put forward, such as those proposed by Gómez-Caro et al.4 (lesions in contact with hilar structures [lobar bronchi, main pulmonary or lobar arteries, main pulmonary veins]) or the American Association of Radiation Oncology5 (lesions located less than 2 cm from the bronchial tree). Although the latter was proposed for the detection of patients at risk of toxicity from stereotactic radiation therapy and not for mediastinal staging purposes, these new definitions added to the confusion surrounding the definition of central tumor location. More recently, evidence-based mediastinal staging guidelines have been published by SEPAR, ACCP, and ESTS, but these recommendations differ widely in the definition of central tumor location. In our study, in answer to the question “What definition do you use to classify a lesion as central?” (question 1), nearly 50% of respondents voted for the definition put forward by Gómez-Caro4 (lesions in contact with the hilum) followed by the ESTS definition (lesions in the two inner thirds) and that of the ACCP (lesions in the inner third). However, when directly comparing the definitions of the ESTS and the ACCP (images 6 and 7), most respondents chose the latter by restricting centrality to the inner third of the hemithorax. Very few respondents chose the definition proposed by SEPAR in answer to question 1, and the “SEPAR central tumor positive control” image was mostly classified as peripheral. These results show that respondents deviate significantly from clinical practice guidelines.

In addition to the lack of uniformity, clinical guidelines are very brief when defining centrally located tumors. This brevity leaves several questions arising in routine clinical practice unanswered, such as: What portion of the tumor should be considered for classification (inner border, outer border, center)? Which lines should be used to delimit the thirds of the lung? How should tumors that extend beyond dividing lines be classified? The second question has historically been answered by using vertical dividing lines parallel to the midline (A lines), as defined by Daly et al.7 However, in 2007, other authors reported using concentric lines arising from the hilum (B lines)8 and more recently Shin et al.9 have used concentric curved lines arising from the midline. In our survey, the lines most widely accepted for demarcating the lung thirds were the B lines, which is in line with the most widely accepted definition of central tumor location (in contact with hilar structures), and shows that most respondents associate a central location with the pulmonary hilum rather than the midline. As for lesions that cross the dividing lines, instead of defining them all as central, most respondents classified them according to the location of the greatest part of their volume.

The role of centrally located tumors as a predictor of mediastinal disease has come under scrutiny since the publication of recent studies showing conflicting results.4,8,10–15 Some authors believe that these disparities may be due to the use of different definitions for central tumor location in each of the studies.16 For this reason, 3 studies using varying definitions of central location have been published in the last 2 years.9,17,18 As a result, none of the definitions proposed in the guidelines was associated with occult mediastinal nodal disease in any of these series. Since tumors greater than 3 cm and N1 tumors in imaging tests are themselves associated with occult mediastinal nodal disease, with N2 disease figures of around 11% and 26%, respectively,19,20 it is important to note that a central location is only an indication for invasive mediastinal staging in the case of pulmonary nodules (T1N0 in imaging tests). In this regard, only 3 studies have included a population exclusively composed of patients with T1N0 tumors in imaging tests.18,21,22 In these series, the prevalence of occult mediastinal nodal disease was low (between 4.7% and 8%) and no association was found between occult disease and tumor location. The role of centrally located tumors in mediastinal staging is therefore controversial, firstly, because of the lack of uniform definitions and, secondly, due to doubts about their association with occult mediastinal disease in patients with T1N0 tumors in imaging tests.

Our study features a significantly higher number of respondents than similar studies,6 but our results, nevertheless, must be interpreted with the same caution as any survey and cannot be considered representative of the entire medical community that treats lung cancer patients in Spain. However, we believe that the lack of a uniform definition of centrality and the discrepancy with clinical guidelines is striking and worthy of reflection.

In summary, this study highlights the lack of uniformity in the definition of central tumor location used by professionals responsible for the management of patients with NSCLC who participated in the survey. It also shows a low adherence by survey respondents to clinical guidelines for certain aspects of central tumor location, mainly in terms of the spatial reference of centrality, determined by the guidelines as the midline yet considered by most survey respondents as the hilum. Despite the limitations of our study, the results reflect the need to include a broader, more uniform definition of centrally located tumors in the next clinical guidelines, if this criterion continues to be specified as an indication for invasive mediastinal staging.

The authors state that they have no conflict of interests.