Abstract
Introduction:
Recent evidence suggests that patients with malignant pleural mesothelioma (MPM) undergoing extended pleurectomy/decortication (eP/D) with metastasis to the posterior intercostal lymph nodes (PILN) have a worse prognosis. In this study, we determine if MPM PILN metastasis can be reliably detected on computed tomography (CT).
Materials and Methods:
Preoperative staging CT exams were reviewed for the presence of PILN in MPM patients undergoing eP/D between 2007–2013 with surgical sampling of their PILN. CT images were reviewed by two thoracic radiologists blinded to clinical records, including operative pathology reports. The number and short axis size of PILN were recorded and correlated with surgical pathology. Statistical analysis examined the value of preoperative CT to detect metastatic PILN.
Results:
Of 36 patients that underwent eP/D with PILN sampling had preoperative CT images for review. At surgery, 22 of these patients had metastatic PILN and 14 had benign PILN. The positive and negative predictive values for one or more nodes seen on preoperative CT were 60% and 38% respectively. The number of PILN on preoperative CT did not predict metastasis (p=0.40) with an average of 2 PILN seen, regardless of PILN pathology. The average nodal short axis size was 4.6 mm and 4.8 mm for benign and malignant PILN, respectively, and PILN short axis size did not predict metastasis (p=0.39). There was little inter-observer variability between the size and number of nodes detected by each radiologist.
Conclusions:
CT does not reliably identify metastatic PILN on preoperative CT for patients with MPM undergoing extended pleurectomy/decortication.
Keywords: CT, posterior intercostal lymph nodes, staging, mesothelioma
Introduction
Malignant pleural mesothelioma (MPM) typically carries a very poor prognosis with most patients succumbing to their disease within 18 months of diagnosis. While controversial, extrapleural pneumonectomy and extended pleurectomy/decortication (eP/D) have been demonstrated to confer a significant survival benefit in certain patient populations.[1, 2] In order to choose the most appropriate treatment option, and thereby achieve the best treatment outcomes, accurate staging of disease is critical.[3] A recent study by Friedberg, et al[4] demonstrated that patients with MPM undergoing (eP/D) had a significantly worse prognosis if they were found to have posterior intercostal lymph nodes (PILN) positive for metastatic MPM at surgery. As a result, it had been proposed that the PILN be included in the MPM staging system. The International Association for the Study of Lung Cancer (IASLC) provides a staging system for MPM, most currently in the eighth edition[5–7]. As part of the changes made to the 8th edition, the PILN lymph nodes are now included as N1 disease[6, 8]. Since the PILN nodal station is now part of the TMN8 staging system for MPM, it is of importance to determine whether metastatic involvement of these nodes can be detected on computed tomography (CT) the primary modality for staging of MPM.
The PILN are located in the posteromedial aspect of each intercostal space (Figures 1 and 2). These lymph nodes drain the ipsilateral parietal pleura, intercostal space and posterior chest wall and, as a result, are at risk for local spread of metastatic disease from the pleural space such as in the setting of MPM.[9, 10] Though the PILN nodes have recently been including into the staging system for malignant pleural mesothelioma, the ability to prospectively detect metastasis in this nodal station on computed tomography (CT), the clinical radiological work-horse for MPM staging, [9–11] has not been assessed.
Figure 1: Axial CT of Posterior Intercostal Space with Pathologic Lymph Nodes.
Intravenous contrast enhanced axial CT cross sectional images of the chest demonstrate a patient with MPM. Enlarged PILN are seen (arrows), confirmed to be metastatic at surgery. The corresponding intercostal artery (arrow heads) is seen traveling adjacent to the observed PILN.
Figure 2: Axial CT of Posterior Intercostal Space with Pathologic Lymph Nodes.
Axial CT cross sectional images obtained, without intravenous contrast enhancement, of a patient with malignant pleural mesothelioma and enlarged posterior intercostal lymph nodes (arrows) with benign PILN at surgery.
Given that the presence of metastasis to the PILN has been proposed to have a significant impact on prognosis in MPM,[10] we sought to explore whether these nodes are detectable on preoperative staging CT and quantify the ability of CT to predict nodal status at surgical staging.
Materials and Methods
Patient population:
Institutional Review Board (IRB) approval, which waived the necessity of patient consent, was obtained through the University of Pennsylvania. A retrospective study was conducted of all consecutive patients with malignant pleural mesothelioma who had undergone radical pleurectomy at Penn Presbyterian Medical Center between the years of 2007–2013 with sampling of their PILN (n=55). Patients without available preoperative staging CT imaging or pathology reports commenting on PILN nodal status were excluded from the study (n=19).
CT review:
CT exams were reviewed retrospectively for the presence of PILN by two board-certified thoracic radiologists with 6 years (R1) and 15 years experience (R2), both of whom were blinded to the clinical charts and operative pathological report, revealing nodal status. Each CT was reviewed and if PILN were visible, the size of the lymph node was measured and the laterality of the node was recorded. All CT exams were analyzed using images with 1–5 mm slice thickness on scanners using 16 detector row or greater. After recording the data for all the patients, the two radiologists reviewed the cases together and discussed discrepancies in discovered lymph nodes. After consensus, any added lymph nodes were measured by the respective radiologist. After completion of recording lymph nodes, comparison of nodal measurements was made to the presence or absence of metastasis in the reported histological analysis of resected PILN surgical specimens.
Statistical Analysis:
Summary statistics were generated for age, sex, race, American Joint Committee on Cancer (seventh edition)[12] for stage, histology, and whether the patient received neoadjuvant chemotherapy. Statistics were also calculated for the number of nodes detected and the 2 dimensional short axis size of the nodes. Sensitivity, specificity, positive predictive value and negative predictive value were determined using a cut point of whether a node was recorded as seen on CT. Logistic regression analysis was used to model the binary pathology status, using node count and average size of the largest two nodes as predictors. ROC analysis followed using both factors. In a separate analysis we examined inter-observer variability in short axis node size using paired comparisons (mixed models) and number of nodes detected (exact test using Poisson counts). Statistical significance was defined as p<0.05.
Results
Patient characteristics:
A total of 36 patients were included in the study. The average patient age was 63.4 years (SD 9.5), and there was a male predominance with 29 males (81%) and 7 (19%) females. Of these 36 patients, 22 patients (60%) had PILN positive for metastasis and 14 patients (40%) had no evidence of malignancy in the surgically sampled PILN. Other patient characteristics are shown in Table 1. There were no significant differences in patient characteristics between patients with PILN metastasis and those without PILN metastasis.
Table 1:
Patient characteristics for the cohort and stratified by metastasis to the PILN.
| Variable, n (%) | Total | Positive PILN, n=22 | Negative PILN, n=14 | p |
|---|---|---|---|---|
| Age, mean (sd) | 63.9 (9.4) | 63.1 (9.9) | 65.5 (8.7) | 0.46 |
| Sex | 0.81 | |||
| Male | 29 (80.6) | 18 (81.8 | 3 (21.4) | |
| Female | 7 (19.4) | 4 (18.2) | 11 (78.6) | |
| Race | 0.32 | |||
| White | 32 (88.9) | 19 (86.4) | 13 (92.9) | |
| Black | 1 (2.8) | 1 (4.6) | 0 (0.0) | |
| Hispanic | 1 (2.8) | 0 (0.0) | 1 (7.1) | |
| Other/unknown | 2 (5.7) | 2 (9.1) | 0 (0.0) | |
| AJCC Stage | 0.20 | |||
| 3 | 21 (58.3) | 11 (50.0) | 10 (71.4) | |
| 4 | 15 (41.7) | 11 (50.0) | 4 (28.6) | |
| Neoadjuvant chemotherapy | 0.45 | |||
| Yes | 13 (36.1) | 9 (40.9) | 10 (71.4) | |
| No | 23 (63.9) | 13 (59.1) | 4 (28.6) | |
| Histology | 0.72 | |||
| Epithelial | 30 (83.3) | 18 (81.8) | 12 (85.7) | |
| Biphasic | 5 (13.9) | 3 (13.6) | 2 (14.3) | |
| Sarcomatoid | 1 (2.8) | 1 (4.6) | 0 (0.0) |
The presence or size of posterior intercostal lymph node was not predictive of nodal metastasis:
The mean number of PILN detected on pre-operative CT in patients with metastatic disease at surgery was not significantly different from the number of PILN detectable on CT in the patients with benign PILN at surgery (p=0.96). Patients with metastatic PILN at surgery had anywhere from 0 to 10 detectable PILN on preoperative CT (average=2.4) compared to a range of 0 to 12 PILN in patients with benign PILN (average=2.4). The sensitivity of a node being present on CT if a patient had metastasis was 55%. The specificity of no nodes being detected on CT if a patient did not have metastasis was 43%. The positive predictive value of metastasis if one or more nodes was identified on preoperative CT was 60%. The negative predictive value of not having metastasis if zero nodes were identified on preoperative CT was 38%. With logistic regression, an increase in the number of nodes did not lead to an increase in predicting metastasis with an odds ratio of 0.90 (p=0.40).
The mean nodal short axis diameter of the PILN by CT was 4.8 mm (SD 1.8 mm) for metastatic nodes compared to 4.6 mm (SD 1.3 mm) for benign nodes. The difference in size between these two groups was not statistically significant (p=0.39). Logistic regression for the combined radiologists found that increasing average size of the two largest nodes by 1 standard deviation had an odds ratio of 1.48 associated with predicting metastasis, but this was not statistically significant (p=0.32). ROC curves were generated to evaluate whether size and number of nodes seen predict metastasis. The area under the curve was 0.52 for the combined radiologists (Figure 3).
Figure 3: ROC Curve for Detecting Metastasis.
ROC curve using regression results and combined with both radiologists for detecting metastasis.
There was little interobserver variability in the detection and measurement of posterior intercostal lymph nodes.
Overall, the number of PILN detected by each of the two radiologists was similar. R2 saw 77 nodes with an average short axis of 4.4 mm (SD 1.6), while R1 saw 83 nodes with an average short axis size of 5.0 mm (SD 1.7). When the same node was compared between radiologists, R1 on average measured the same node 0.5 mm larger, a statistically, but not clinically, significant difference (p=0.002).
Discussion
This study represents the first assessment of the potential value of CT to detect metastasis to the PILN on CT in any malignancy. Until recently, PILN were not included in any cancer staging system, and they were not appreciably discussed in the literature. As a result, the vast majority of radiologists do not comment on this nodal group. Recently, Friedberg et al demonstrated that patients with MPM with metastasis to the PILN have a significantly worse prognosis.[4, 13] The PILN nodal group has subsequently be included in the most recent version of the IASLC staging system for MPM (8th edition)[6, 8]. As such, there is value in determining if CT can reliably detect and characterize metastatic disease to the PILN, which would be valuable to accurate pre-operative staging, or whether this is a surgical diagnosis. While the presence of N1 nodal disease denoted by the presence of metastatic PILN would not likely alone preclude surgical resection, it does impact prognosis and the accuracy of pre-operative prognostication. While nodal dissection of the PILN nodal station is not uniformly routinely practiced during pleurectomy for MPM, this is likely to change in the future given its recent inclusion in the TMN staging system for MPM.
Our results demonstrate that presence of PILN on preoperative CT may not be a useful tool to determine the presence of metastatic disease to the PILN in patients with MPM. The average nodal size was similar in patients with and without metastasis to their PILN. We hypothesize that the prominence of these nodes in benign disease is on the basis of reactive changes. It is possible that with a larger sample size, a difference in short axis size between the two groups may have become significant; however, these preliminary results suggest that CT will be of marginal predictive value for staging of this nodal group as the short axis difference was only minimally greater and within the margins of inter-observer measurement variability.
A conventional threshold of 10 mm for short axis size, above which nodes are considered suspicious for malignancy, is also unlikely to be value for the PILN.[14] In our study, using a 10 mm threshold for short axis dimension, only one PILN would be considered suspicious for malignancy, despite the numerous metastatic PILN detected at surgery. As has been suggested in the literature, the use of 10 mm in short axis as a size threshold on CT is anticipated to result in significant underestimation of disease.[15]
In a study conducted by Heelan et al,[16] the area under the ROC curve for CT to detect nodal involvement in MPM was 0.51. Their results mirror our ROC results. However, better results have been reported.[17] In our study, there was some inter-observer variability between the two thoracic radiologists in the measurement and detection of PILN on CT. There was a 0.5 mm difference in the nodal measurements between the two thoracic radiologists when measuring a specific PILN. However, this very small size difference is not clinically significant. The difference in number of nodes seen by each radiologist is comparable to reports of inter-observer agreement between the radiologists on thoracic lymph nodes on CT published in the literature. For example McErlean et al [18] reported inter-observer agreement among 17 radiologists for lung lymph nodes was estimated at 88%. Frauenfelder et al [15] found the inter-observer variability for N staging between radiologists to be “moderate” at best.
Our results suggest that CT is of limited value for the preoperative detection of metastasis to the PILN in patients with MPM. Other potential imaging modalities that are often employed in preoperative staging of MPM include FDG-PET/CT (18F-fluorodeoxyglucose-positron emission tomography/ computed tomography) and magnetic resonance imaging (MRI). Given their small size and location in close proximity to pleural tumor, it seems less likely that FDG-PET/CT will be of added value in characterization of this nodal group. In addition to limitations in spatial resolution, given that the PILN are enlarged in benign disease, they are likely to also be FDG-avid due to reactive changes. While MRI has superior soft tissue contrast to CT, it is unlikely to be helpful in discriminating between benign and malignant disease since the size and number of the PILN are not significantly different between benign and malignant disease on CT. However, it will be important to fully assess the sensitivity and specificity of both MRI and FDG-PET/CT for the detection of malignant PILN in preoperative staging and this is an important future direction for study.
There are several limitations to our study. Patients were classified as having benign or metastatic PILN based on the PILN sampled at surgery. These resected PILN were detected by intraoperative palpation and exploration. Since specific intercostal levels were not indicated for the resected PILN, we were unable to correlate a specific node seen on imaging to a specific node on pathology. As a result, it is possible that an enlarged metastatic PILN detected on CT was not sampled at surgery and falsely deemed “benign.” However, in our experience, intraoperative sampling was complete and clinical comprehensive, but exhaustive sampling of every PILN would not be feasible. Also, the anatomical location of PILN does not make these nodes readily accessible by CT guided biopsy. Since our study primarily employed CT images with 5 mm slice thickness, it is possible that some small PILN, less than 5 mm in size, could be missed due to volume averaging. However, since 5 mm thick slice thickness is a conventional CT protocol for imaging of the chest, this work is believed to be generalizable and representative of conventional preoperative CT staging[11].
In conclusion, while metastatic PILN detected at surgery may have prognostic significance in patients with MPM, this study demonstrates that metastasis to this nodal group cannot reliably by detected by CT. If PILN metastasis is to be used in staging and decision-making, future studies should focus on different imaging modalities to per-operatively predict the patients with metastasis.
HIGHLIGHTS.
Posterior intercostal node (PILN) metastasis portends poor outcome in mesothelioma.
The PILN nodal group has recently been incorporated into the TMN staging system.
CT is not sensitive or specific for detecting PILN metastasis in mesothelioma.
Assessment of PILN nodal status is likely a surgical diagnosis in mesothelioma.
Acknowledgments
Conflict of interest Statement
There are no conflicts of interest for the authors. This research was supported by funding through the NIH (5P01CA08797113).
Abbreviations:
- PILN
posterior intercostal lymph nodes
- MPM
malignant pleural mesothelioma
- CT
computed tomography
- FDG-PET/CT
(18F-fluorodeoxyglucose-positron emission tomography/computed tomography)
- MRI
magnetic resonance imaging
- ROC
receiver operator curve
Footnotes
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References
- [1].Cao C, Tian D, Park J, Allan J, Pataky KA, Yan TD, A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma, Lung Cancer 83(2) (2014) 240–5. [DOI] [PubMed] [Google Scholar]
- [2].Rusch VW, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, Pass H, Asamura H, Waller D, Edwards J, Weder W, Hoffmann H, van Meerbeeck JP, Committee IS, Initial analysis of the international association for the study of lung cancer mesothelioma database, J Thorac Oncol 7(11) (2012) 1631–9. [DOI] [PubMed] [Google Scholar]
- [3].Muers MF, Stephens RJ, Fisher P, Darlison L, Higgs CM, Lowry E, Nicholson AG, O’Brien M, Peake M, Rudd R, Snee M, Steele J, Girling DJ, Nankivell M, Pugh C, Parmar MK, Group MSTM, Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial, Lancet 371(9625) (2008) 1685–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Friedberg JS, Simone CB 2nd, Culligan MJ, Putt ME, Barsky AR, Katz S, Cengel KA, Posterior Intercostal Lymph Nodes Double Recurrence and Death Risk in Malignant Pleural Mesothelioma, Ann Thorac Surg (2019). [DOI] [PubMed] [Google Scholar]
- [5].Nowak AK, Chansky K, Rice DC, Pass HI, Kindler HL, Shemanski L, Bille A, Rintoul RC, Batirel HF, Thomas CF, Friedberg J, Cedres S, de Perrot M, Rusch VW, Staging AB Prognostic Factors Committee, I. Participating, The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma, J Thorac Oncol 11(12) (2016) 2089–2099. [DOI] [PubMed] [Google Scholar]
- [6].Rice D, Chansky K, Nowak A, Pass H, Kindler H, Shemanski L, Opitz I, Call S, Hasegawa S, Kernstine K, Atinkaya C, Rea F, Nafteux P, Rusch VW, Mesothelioma IS Domain of the, a.b. Prognostic Factors Committee, i. participating, The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma, J Thorac Oncol 11(12) (2016) 2100–2111. [DOI] [PubMed] [Google Scholar]
- [7].Rusch VW, Chansky K, Kindler HL, Nowak AK, Pass HI, Rice DC, Shemanski L, Galateau-Salle F, McCaughan BC, Nakano T, Ruffini E, van Meerbeeck JP, Yoshimura M, Staging I, a.b. Prognostic Factors Committee, i. participating, The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma, J Thorac Oncol 11(12) (2016) 2112–2119. [DOI] [PubMed] [Google Scholar]
- [8].Berzenji L, Van Schil PE, Carp L, The eighth TNM classification for malignant pleural mesothelioma, Transl Lung Cancer Res 7(5) (2018) 543–549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Nickell LT Jr., Lichtenberger JP 3rd, Khorashadi L, Abbott GF, Carter BW, Multimodality imaging for characterization, classification, and staging of malignant pleural mesothelioma, Radiographics 34(6) (2014) 1692–706. [DOI] [PubMed] [Google Scholar]
- [10].Rusch VW, A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group, Chest 108(4) (1995) 1122–8. [DOI] [PubMed] [Google Scholar]
- [11].Gill RR, Tsao AS, Kindler HL, Richards WG, Armato SG 3rd, Francis RJ, Gomez DR, Dahlberg S, Rimner A, Simone CB 2nd, de Perrot M, Blumenthal G, Adjei AA, Bueno R, Harpole DH Jr., Hesdorffer M, Hirsch FR, Pass HI, Yorke E, Rosenzweig K, Burt B, Fennell DA, Lindwasser W, Malik S, Peikert T, Mansfield AS, Salgia R, Yang H, Rusch VW, Nowak AK, Radiologic Considerations and Standardization of Malignant Pleural Mesothelioma Imaging Within Clinical Trials: Consensus Statement from the NCI Thoracic Malignancy Steering Committee - International Association for the Study of Lung Cancer - Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting, J Thorac Oncol 14(10) (2019) 1718–1731. [DOI] [PubMed] [Google Scholar]
- [12].Edge SB BD, Compton CC, Fritz AG, Greene FL, Trotti A, AJCC cancer staging manual (7th ed). Springer, New York, NY: 2010. [Google Scholar]
- [13].Friedberg J, Culligan M, Putt M, Hahn S, Alley E, Simone C, Sterman D, Cengal K, Posterior Intercostal Lymph Nodes - First Report of a New Independent Prognostic Factor for Malignant Pleural Mesothelioma, 15th World Conference on Lung Cancer, Journal of Thoracic Oncology, Sydney, Australia, 2013. [Google Scholar]
- [14].Ganeshalingam S, Koh DM, Nodal staging, Cancer Imaging 9 (2009) 104–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Frauenfelder T, Kestenholz P, Hunziker R, Nguyen TD, Fries M, Veit-Haibach P, Husmann L, Stahel R, Weder W, Opitz I, Use of computed tomography and positron emission tomography/computed tomography for staging of local extent in patients with malignant pleural mesothelioma, J Comput Assist Tomogr 39(2) (2015) 160–5. [DOI] [PubMed] [Google Scholar]
- [16].Heelan RT, Rusch VW, Begg CB, Panicek DM, Caravelli JF, Eisen C, Staging of malignant pleural mesothelioma: comparison of CT and MR imaging, AJR Am J Roentgenol 172(4) (1999) 1039–47. [DOI] [PubMed] [Google Scholar]
- [17].Schouwink JH, Kool LS, Rutgers EJ, Zoetmulder FA, van Zandwijk N, v d Vijver MJ, Baas P, The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma, Ann Thorac Surg 75(6) (2003) 1715–8; discussion 1718–9. [DOI] [PubMed] [Google Scholar]
- [18].McErlean A, Panicek DM, Zabor EC, Moskowitz CS, Bitar R, Motzer RJ, Hricak H, Ginsberg MS, Intra- and interobserver variability in CT measurements in oncology, Radiology 269(2) (2013) 451–9. [DOI] [PubMed] [Google Scholar]