記住我
ORIGINAL ARTICLE
Year : 2023 | Volume
: 22
| Issue : 1 | Page : 101-106
Positron emission tomography - Computed tomography for staging of mediastinal lymph nodes in patients with non-small cell lung cancer
Georgi Prisadov1, Anja Blume-Vulin2, Martin Scharpenberg3, Katrin Welcker4, Emeka Blessius Kesieme5, Albert Linder6
1 Clinic of Thoracic Surgery, Maria Hilf Hospital, Mönchengladbach, Germany; Department of Special Surgery, Medical University of Plovdiv, Plovdiv, Bulgaria
2 Lung Cancer Center, Bremen East Clinic, University of Bremen, Bremen, Germany
3 Competence Center for Clinical Studies, University of Bremen, Bremen, Germany
4 Clinic of Thoracic Surgery, Maria Hilf Hospital, Mönchengladbach, Germany
5 Department of Cardiothoracic Surgery, Golden Jubilee National Hospital, Glasgow, Scotland
6 Clinic of Thoracic Surgery, St. Anna Clinic, Lucerne, Switzerland
Correspondence Address:
Georgi Prisadov
Erlenweinstr 19-A, 47829 Krefeld
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aam.aam_12_22
Abstract
Background: The tumor involvement of lymph nodes (LN) in N2 station is a very important factor for the further therapy decision and the prognosis of lung cancer patients. Today, integrated positron emission tomography-computed tomography (PET-CT) is considered to be the new standard in the staging of bronchial carcinoma. The aim of this study is to investigate the correctness of the clinical staging of the mediastinal LNs in operated patients and to investigate the sensitivity and specificity of the PET-CT examination for mediastinal LNs. Subjects and Methods: In the years 2010–2014, 359 patients underwent surgery for bronchial carcinoma. The histological examination of all mediastinal and hilar LNs was used as a reference to the data from the PET-CT examinations. The correctness of the PET staging, overestimation, and underestimation for the N stage was analyzed. In addition, the “sensitivity,” “specificity,” and “overall accuracy” of the PET-CT examination with regard to the N2 LNs were calculated. Results: It was found that in 8.9% the staging of the mediastinal N2/N3 LN stations was rated too high by the PET and in 11.2% too low. The study showed a sensitivity of 47.37%, a specificity of 90.07%, and an accuracy of 81.01% for the mediastinal LNs. Conclusion: Our study confirms the limited ability of integrated PET-CT in staging the mediastinal LNs. We, therefore, recommend a histological examination of the LNs in patients with PET-positive N2 LNs to avoid false-positive results and to initiate correct therapy.
Abstract in French Résumé
Contexte: L'implication tumorale des ganglions lymphatiques (LN) au stade N2 est un facteur très important pour la décision thérapeutique ultérieure et le pronostic des patients atteints de cancer du poumon. Aujourd'hui, la tomographie par émission de positons intégrée (TEP-CT) est considérée comme être la nouvelle norme dans la stadification du carcinome bronchique. Le but de cette étude est d'étudier l'exactitude de la stadification clinique des ganglions lymphatiques médiastinaux chez les patients opérés et d'étudier la sensibilité et la spécificité de l'examen TEP-TDM pour les ganglions lymphatiques médiastinaux. Sujets et méthodes: Dans les années 2010 à 2014, 359 patients ont été opérés d'un carcinome bronchique. L'examen histologique de tous les LN médiastinaux et hilaires a servi de référence aux données des examens PET-CT. La justesse de la mise en scène PET, la surestimation et la sous-estimation pour le stade N ont été analysées. De plus, la “ sensibilité “, la “ spécificité “ et la “ précision globale “ de l'examen PET-CT en ce qui concerne les N2 LNs ont été calculés. Résultats: Il a été constaté que dans 8,9 % des cas, la mise en scène du médiastin N2/ Les stages N3 LN ont été jugées trop élevées par le PET et dans 11,2 % trop faibles. L'étude a montré une sensibilité de 47,37%, une spécificité de 90,07%, et une précision de 81,01 % pour les LN médiastinaux. Conclusion: Notre étude confirme la capacité limitée de la TEP-TDM intégrée dans la stadification les LN médiastinaux. Nous recommandons donc un examen histologique des ganglions lymphatiques chez les patients avec des ganglions lymphatiques N2 positifs à la TEP pour éviter résultats faussement positifs et d'initier un traitement correct
Mots-clés: Cancer du poumon, tomographie par émission de positrons/tomodensitométrie, stadification
Keywords: Lung cancer, positron emission tomography/computed tomography, staging
Introduction 
Lung cancer is the most prevalent malignant tumor worldwide and the third most common cause of death after ischemic heart failure and acute myocardial infarction. For males, it is the leading cause of death, while in females the non-small cell lung cancer (NSCLC) ranks in sixth place as the cause of death. In recent years, a decline in incidences in males has been observed, whereas the incidence in females has almost tripled since the 1980s.[1]
Characteristics of NSCLC are early lymphogenic metastases. Approximately 10% of patients diagnosed with NSCLC present with advanced tumor stages with mediastinal (N2-N3) lymph node (LN) metastases, of which 30%–35% show no hilar (NI) LN metastases.[2] The LN involvement in stage N2 is not only an important factor for the correct staging, but also decision-making pertaining to the treatment and the prognosis of the patient. The therapeutic course of action in these patients still poses a major challenge and requires an interdisciplinary approach. Thus, a precise staging is crucial for the choice of the proper treatment and its success.
Further investigation of enlarged or suspicious mediastinal LNs is accomplished by noninvasive imaging methods, such as thoracic computed tomography (CT), positron emission tomography (PET), and PET-CT, as well as invasive procedures, like bronchoscopy with endobronchial ultrasound-guided fine-needle aspiration biopsy (EBUS-FNAB, esophagoscopy with endoscopic ultrasound-guided FNAB, video-assisted mediastinoscopic lymphadenectomy (VAMLA), and video-assisted thoracoscopic surgery, having varying degrees of sensitivity and specificity.[3],[4],[5],[6]
Despite the exclusion of mediastinal LN metastases after preoperative staging, surgery reveals ipsilateral mediastinal LN metastases in 25% of patients.[2]
Given that Stage IIIA includes operable and inoperable tumors and surgery constitutes the only curative treatment option, the aim should be not to deny any potentially curable NSCLC patient a surgical treatment.
Our retrospective study is concerned with this issue. The aim of the study is to assess the correctness of clinical staging of mediastinal LNs in operated patients or rather to ascertain the sensitivity and specificity of PET/CT investigations.
Subjects and Methods Study group
During the years 2010–2014, 359 patients have been operated for NSCLC in the department of thoracic surgery at our hospital. The study included 247 men and 112 women aged 42–86-year-old (mean age of 66.3 years).
Initially, the study was conducted from 2010 to 2013 and comprised 245 patients. Later, 114 patients from 2014 were added to the study group. For better comparison, some data were statistically analyzed separately.
Methodology of clinical and postoperative-pathological staging
In the context of clinical staging, in addition to thoracic CT and bronchoscopy, all patients received a PET-CT under standardized conditions. The staging of the tumor was determined pursuant to the 7th edition of tumor-node-metastasis (TNM) classification and therapy was planned accordingly.
During data acquisition in the lung cancer center, for patients with PET-positive N2 LNs, mediastinoscopy was only performed if it was a multi-level N2 stage and anamnestic silicotic or specific LN-changes were suspected. EBUS-transbronchial needle aspiration was not in use until 2015. In case of multi-level N2 stage, patients were treated by radio- and chemotherapy. Pulmonic and radiologic oncologists considered induction chemotherapy and subsequent surgery nonreasonable.
The histology of all mediastinal and hilar LNs was correlated to data of PET-CT examinations. False-negative mediastinal LNs were re-assessed in detail. All LNs were excised after a standardized clinic-specific technique. On the right-side lymphatic and adipose tissue of station, two and four were dissected along the superior vena cava, ascending aorta, trachea, and vagal nerve. The left paratracheal LNs were spared unless they were enlarged on CT. LNs in the tracheobronchial angle and aortopulmonary window were resected with great care to avoid damaging the recurrent laryngeal nerve. Both main bronchi were displayed and around 2 cm of the subcarinal region was dissected along the pericardium and the esophagus, in doing so, the paraesophageal LNs were generally removed. Hilar and interlobar LNs were separated from bronchi and vessels and excised with the affected lobe of the lung. Dissected LNs were screened histologically, staging-appropriate, for tumor cells. The resultant pN-stage was used as a reference for the sensitivity of PET-CT-generated cN-stages.
The department of pathology performed the histopathologic examination of the excised primary tumors and LNs. In addition to standard dyes used for differentiation between histologic subtypes of NSCLC, immunohistochemistry was performed. Tumor size, TNM-staging, grading, and typing were compiled.
The study took TNM-staging and histologic subtypes into consideration.
Statistical analysis
The evaluation was mainly based on frequency analysis and performed in the competence center for clinical trials. The analysis focused on the correctness of PET-staging, overestimation, and underestimation of the overall N-staging, as well as the staging of individual LNs.
Furthermore, the “sensitivity” (number of true positives/number of true positives + number of false negatives), “specificity” (number of true negatives/number of true negatives + number of false positives), and “overall accuracy” of PET-CT investigations regarding N2- LNs were calculated.
Results The study included 359 patients within the age range of 42–86 years and an average age of 66.3 years. VAMLA was performed in 38 of the patients to precisely stage the mediastinal LNs. Multi-N2-metastases were histologically proven in 24 out of those 38 cases, while one case was N3-metastases. These patients received a combination of radio and chemotherapy. The remaining 13 patients showed “single-level” N2-metastases and were treated with radical surgery. In 334 patients, a radical, curative resection of the primary tumor with mediastinal lymphadenectomy was performed. The characterization of patients and primary tumors is shown in [Table 1].
The percentage of females added up to 29.39% in the first study group (2010–2013) and 35.09% in the second (2014). Male patients accounted for 70.61% in the first and 64.01% in the second group, which depicts the regressing incidence in males and the rising incidence in females.
Adenocarcinomas were predominating the second study group (2014) with 56.14%, whereas adenocarcinomas (48.51%) and squamous cell carcinomas (49.36%) were almost balanced in the first group (2010–2013).
The percentage of patients with diabetes mellitus was much larger in the first group of patients (21.63%) as compared to the second group (14.04%).
The most frequently conducted operation, and treatment of choice, in both study groups was lobectomy. In both the study groups, VAMLA was performed in 10.6% of patients.
Prognosis based on positron emission tomography N-staging
As before mentioned, the histologic results were the evidence used as the basis of the assessment of the PET-CT investigations, in evaluating the correctness of the N-classification. The comparison between histology and PET-CT results showed the preciseness of preoperative staging.
[Table 2] shows the true-and false-positive and the false-negative results of clinical staging of LNs in absolute numbers. Thus, it appears that the PET staging was correct in 218 cases (61.06%). Regarding the N2/N3 stages, the clinical N-staging was found to be false negative in 40 patients (11.2%) and slightly higher than the number of false positive in 32 patients (8.9%). The involvement of the N1- LNs was staged as false negative in 61 patients (17.1%) and false positive in only 6 (1.7%); hence, the fraction of false-negative cases was 10 times higher. Therefore, 8.9% of cases were overestimated and 11.2% underestimated in the clinical staging of N2/N3 LN involvement. N1-LNs were under-staged in 17% of cases by the PET.
Table 2: Comparison of N-staging gained by histologic and positron emission tomography-computed tomography investigations in the common study groupComparing stage N0/N1 classification (hereinafter “negative”) and stage N2/N3 classification (hereinafter “positive”) allow for the calculation of sensitivity (number of true positives/[number of true positives + number of false negatives]) and specificity (number of true negatives/[number of true negatives + number of false positives]) of the PET regarding the mediastinal LNs.
[Table 3] depicts the direct comparison between sensitivity and specificity of PET-CT for individual years, as well as values for the overall study group. All in all, the sensitivity adds up to 47.37%, the specificity to 90.07%, and the accuracy to 81.01% [Table 3].
Table 3: Sensitivity and specificity of positron emission tomography-computed tomography regarding mediastinal lymph nodes[Diagram 1] represents the sensitivity, specificity, and accuracy of PET over the course of the study. It shows the regression of the above-mentioned parameters between the years 2010 and 2012 with an all-time low in the latter. Since 2012, sensitivity, specificity, and accuracy showed an increasing trend reaching a maximum value in 2014 for this study.
Potential factors of influence for positron emission tomography-sensitivity
The compiled data contain a series of factors (age, body mass index, blood glucose, standardized update value (SUV), gender, grading, LN-station, N-classification, and atelectasis) that might alter the quality of the prognosis set by PET-CT. The specificity is assumed to be sufficient, and the following paragraphs are concerned with the sensitivity in particular.
Logistic regression, with the dependent variable “PET-positive,” was performed for each factor, to determine which variables impact the sensitivity. This group of results presents all LN stations with positive histologic reports.
The analysis and associated P values must be considered explorative because there was no adjustment made for compliance with the multiple errors of the first degree.
From the results of this analysis, it could be concluded that, in contrast to former assumption, SUV as well as blood glucose had no statistically significant influence on PET-CT sensitivity.
The categorical co-variables that showed a significant impact on the sensitivity of the PET are the N-classification of the LNs (N1 or N2) (P = 0.0366) and the anatomical position of LNs (P = 0.0485). The results show that the sensitivity of PET-CT-investigations is higher in the N2-LN-position compared to the N1-position.
Discussion More than 1 million people die of lung cancer each year. The long-term survival has barely improved within the past 30 years, despite new developments in diagnosis and treatment.[1]
As mentioned in the introduction the clinical staging is based on various noninvasive and invasive investigative methods. This clinical staging is the foundation of decision-making regarding prospective treatment. Mediastinal LN metastases are notably the most important to decide between a primary curative surgery or other available therapies.
During the 1990s, computed tomography used to be the imaging method of choice for preoperative staging.[3] Literature denotes the accuracy of CT with 57% sensitivity and 82% specificity.[5],[6] Especially the sensitivity of the CT examination for affected N2-lymph nodes is too low.[7] The evaluation of LNs using the CT is dependent on their size. The cutoff value between normal and pathologically enlarged LN is 1 cm in diameter.[3],[8] From a practical point of view; this parameter has proven to be unreliable for the staging of LN metastases. On the one hand, enlarged LNs can be benign, while on the other hand, normal-sized LNs can contain micrometastases and remain undetected. Due to this fact, 8%–60% of regular-sized LN later revealed microscopic metastases.[8],[9]
Nowadays, PET-CT is considered the new standard.[10] The benefit of this imaging method is the combined visualization of biochemical function (PET) and morphology (CT). It presents the same time information about the metabolism and anatomy of tissues. By means of using the integrated PET-CT, the diagnostic accuracy of the tumor staging is higher than separate CT or PET regarding T- and N-stages. Furthermore, PET-CT is superior in the detection of mediastinal LNs compared to CT.[10],[11]
This study focuses on LN staging of the mediastinal LNs. Robinson et al. divide IIIA patients with N2 situation into subgroups IIIA1-4 with regard to the therapeutic approach. This subdivision helps to choose the correct therapeutic approach in the various IIIA (N2) situations.[12] Precisely because IIIA stage includes a very different group of patients and the forms of therapy (surgical resection vs. radio-chemotherapy) vary greatly within this group, correct clinical staging at this UICC stage is of particular importance.[13]
During data acquisition in our center for lung cancer, only patients with positive multi-level-N2-results in PET-CT and anamnesis raising suspicion of silicotic or specific LN-changes underwent a mediastinoscopy. EBUS was not in use in our center for lung cancer until 2015. In case of multi-level-N2 situation, the patients were treated with a combination of radio and chemotherapy. Induction chemoradiotherapy with subsequent surgery was considered nonreasonable by our pneumological oncologists. With this strategy, the fluorodeoxyglucose (FDG)-PET gains more importance in the therapeutic approach in our center compared to those centers, for example, for N2-cases, perform surgery after neoadjuvant therapy, since we prevent false-positive PET N2-staged patients, from receiving curative surgery.
Data for comparison between PET and mediastinoscopy were retrieved from a heterogeneous group of multilevel-N2, in which silicotic or specific LN-changes were suspected from the anamnesis.
The statistical data of all patients, which were diagnosed and treated according to above-mentioned criteria, are of utmost importance in a center for lung cancer. Thus, the data regarding the sensitivity and specificity of FDG-PET in day-to-day clinical workflow was calculated for the total number of operated patients, i.e., “PET use in real life.” No patients were excluded from PET scans or this analysis for any reason, such as diabetes, elevated fasting blood glucose, restlessness, poor general condition, or a primary tumor with little to no acceleration in metabolism. Histologic examination of all mediastinal and hilar LNs was used as a reference to the PET data. As mentioned above, all LNs were excised following uniform clinic-specific procedures. The results of histologically generated pN-stage were used as a reference for the sensitivity of PET-generated cN-stages. The following values have been calculated: sensitivity: 47.37%, specificity: 90.07%, false positive: 8.9%, false negative: 11.2%.
The false negative LNs were re-assessed by pathologists. Re-examination often revealed LN larger than 10 mm in diameter with subtotal or total tumor invasion, meaning that they were not micrometastases. Some LNs showed partial or subtotal necrosis. From a pathohistological point of view, this might explain some of the false-negative results.
Literature provides many studies that report different specificities and sensitivities for PET-CT investigations.
[Table 4] shows a summary of the compared studies. One significant difference between the results of various researchers is the determination of the optimal cut-off threshold for SUV values.
Furthermore, the time between the injection of radionucleotide and the start of PET investigation varied among studies.
The problem of absent standards in the acquisition of data and image reconstruction was recognized by the professional society and improved by an up-to-date guideline.[14]
Li et al.[15] reported 13.2% false-negative and 45.6% false-positive results using an SUV cutoff of 2.34.
Al-Sarraf et al.[16] reported occult N2-metastases with a frequency of 16%. Similar results (14% occult N2-metastases) were presented by Cerfolio et al.[4]
According to Lee et al.,[17] some risk factors exist for occult N2-metastases. They include adenocarcinoma, tumors in the upper lobe, large tumors, high SUVmax (>4.0) of the primary tumor, centrally located tumors, N1-positive nodes in PET-CT, and poorly differentiated tumors.
Pelosi et al.[18] report 10.5% false-negative N2-LNs. The most common reason was the small size of metastases (<10 mm, micrometastases). In 84.6% of cases with false-negative N2-LNs, the primary tumor was an adenocarcinoma. The most frequently “hidden” metastases were found in station 7 (22.2%), followed by the right paratracheal LNs.
Li et al.[15] specify the invasion of visceral pleura as a risk factor for occult N2-LN metastases. A possible reason, according to the authors, might be the high prevalence of lymph vessels in the visceral pleura and their close interaction.[19],[20]
Pelosi et al.[18] report 8.5% false-positive N2-results, compared to Li et al.[15] with 45.6%. These false positives can be caused by reactive hyperplasia, active inflammation, granulomatous diseases, silicon anthracosis, or tuberculosis. The studies at hand consider the patient's age, differentiation of tumors, low SUVmax of primary tumor, and nonadenocarcinomas as risk factors for false-positive results.[21],[22],[23]
In summary, the above-mentioned authors[14],[16],[17],[18],[24],[25],[26] considered the accuracy of PET-CT to be insufficient to replace mediastinoscopy. They recommend a histological examination by mediastinoscopy, in case of PET-positive N2-LNs, to avoid false-positive results.
Vest et al.[27] show that invasive staging is rarely used. Most patients in stage IIIA did not receive the appropriate mediastinal LN-staging.
Some authors think that negative PET-CT results in patients with increased possibility of LN metastases do not make invasive staging methods redundant.[28],[29],[30]
Our results are comparable to the findings of Pelosi et al.,[18] Perigaud et al.[31] and Suh et al.[32]
Conclusion Our study confirms the limited ability of integrated PET-CT in the staging of mediastinal LNs in patients with potentially operable NSCLC. If the stage-related treatment choice is made entirely based on PET-CT staging, the chance that a patient is refused a proper treatment because of false-positive results is 8.9%. Thus, we advise histologic clarification of LNs in patients with N2-positive PET scans to avoid false-positive results and to initiate the correct treatment.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
留言 (0)