|Ahead of print
Evaluation of 18FDG PET-CT-positive mediastinal-hilar lymph nodes in extrathoracic malignancies by EBUS-TBNA; correlation of SUVmax, and short-axis diameter with the final diagnosis
Kunal Luthra, Jyoti Singh
Department of Chest and Respiratory Medicine, Delhi State Cancer Institute, Delhi, India
|Date of Submission||30-Jul-2019|
|Date of Decision||12-Nov-2019|
|Date of Acceptance||16-Nov-2019|
|Date of Web Publication||30-Sep-2021|
Department of Chest and Respiratory Medicine, Delhi State Cancer Institute, Delhi
Source of Support: None, Conflict of Interest: None
Introduction: Intrathoracic lymph node metastasis from extrathoracic neoplasms are rare. Primary malignancies that metastasize to mediastinal-hilar lymph nodes are head and neck , carcinoma breast ,and genitourinary. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)/endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is currently the preferred modality for mediastinal lymph node sampling.
Methods: Fifty seven patients with extrathoracic malignancies with maximum standardized uptake value (SUVmax) of mediastinal-hilar lymph nodes greater than or equal to 2.5 were taken up for EBUS-TBNA. The histo-cytopathological results obtained from EBUS-TBNA were compared with SUVmax value and short-axis diameter of a lymph node as noted on EBUS.
Results: Out of 74 sampled nodes, 49 (66.2%) were benign and 25 (33.8%) were malignant. The SUVmax range of benign nodes was 2.8–13 as compared to 3–18 of malignant nodes. The size range of malignant and benign nodes were 8–35 mm and 8–30 mm, respectively. The mean size of abnormal nodes (metastatic + granulomatous) was 17.5 (8–35 mm) and the mean SUVmax was 9.1 (3.4–18), and it was a statistically significant difference when compared to reactive (normal) nodes. At SUVmax cut-off 7.5, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) were 78.5%, 81.2%, 84.6%, and 74.2%, respectively for detecting abnormal nodes. At 13 mm size cut-off, sensitivity, specificity, PPV, NPV were 75.5%, 65%, 75%, and 72%, respectively, for detecting abnormal nodes.
Conclusion: The majority of mediastinal-hilar nodes with increased metabolic activity are benign in nature. Size and SUVmax are poor predictors of metastasis in tuberculosis endemic region. There should be a restrictive attitude toward invasive diagnostic testing for mediastinal-hilar nodes in extrathoracic malignancies.
Keywords: 18FDG PET-CT scan, endobronchial ultrasound-guided transbronchial needle aspiration, extrathoracic malignancy, mediastinal-hilar node, short-axis diameter, SUVmax
Mediastinal hilar lymph nodes with increased metabolic activity are mostly benign in nature in extrathoracic malignancies.
|How to cite this URL:|
Luthra K, Singh J. Evaluation of 18FDG PET-CT-positive mediastinal-hilar lymph nodes in extrathoracic malignancies by EBUS-TBNA; correlation of SUVmax, and short-axis diameter with the final diagnosis. Indian J Cancer [Epub ahead of print] [cited 2022 May 25]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=327235
| » Introduction|| |
Intrathoracic lymph node metastasis from extrathoracic neoplasms are rare. Primary malignancies that metastasize to mediastinal-hilar lymph nodes are head and neck , carcinoma breast ,and genitourinary., Positron emission tomography with a 2-deoxy-2-fluorine-18-fluoro-D-glucose (18FDG PET-CT) scan, an integral component in the management of cancer, is utilized for diagnosis, staging, restaging, and assessment of treatment response. PET-CT cannot differentiate clearly between benign and malignant mediastinal nodes based on maximum standardized uptake value (SUVmax), especially in settings where granulomatous diseases are common. SUVmax cut-off 2.5 and above give more optimal results in routine practice, higher cut-off value has more specificity and diagnostic accuracy in determining mediastinal-hilar node metastasis in developing countries., The short-axis diameter of the lymph node is a predictor of metastasis, the longer the axis more the probability of metastasis. A short-axis diameter greater than 1.42 cm (measured on endobronchial ultrasound [EBUS]) provides the best sensitivity and specificity for predicting malignant node., Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)/endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a minimally invasive procedure, with high diagnostic accuracy and currently the preferred modality for mediastinal lymph node sampling., Mediastinal nodes can be evaluated through the esophageal route with EBUS scope (EUS-B). EUS-B can assess lower mediastinal nodes in addition to left paratracheal and subcarinal nodes. EBUS-TBNA can reach right, left paratracheal, subcarinal, hilar, and interlobar nodes as well. If the combination is not available, EBUS-TBNA alone is accepted for staging. If a patient is unfit for EBUS-TBNA procedure due to hypoxemia, potential airway compromise, or excessive coughing, then EUS-B FNA can be used. Similar practices are being mentioned in other studies as well, where EUS-B FNA is rarely used. There was no patient in our study where EUS-B FNA was done.
EBUS-TBNA is a safe procedure that can be done under conscious sedation; complications, if observed, are minimal and self-limiting. Major complications include respiratory failure, arrhythmia, and hypotension seen in 1.1% of cases. Minor complications include transient chest pain, chills, and excessive coughing seen in 0.2%, 0.5%, and 1.4% cases, respectively. In this study, we correlated the results of EBUS-TBNA of mediastinal-hilar lymph nodes in extrathoracic malignancies with SUVmax uptake in 18FDG-PET scan and size of a lymph node in endobronchial ultrasound to determine the cut-off with high specificity and diagnostic accuracy in predicting metastasis.
| » Materials and Methods|| |
We retrospectively analyzed the results of EBUS-TBNA done for mediastinal-hilar lymphadenopathy at our institute. Inclusion criteria were a recent PET scan at the time of the procedure with SUVmax of mediastinal lymph nodes greater than or equal to 2.5, known case of extra-thoracic malignancy. The histo-cytopathological results obtained from EBUS-TBNA were compared with SUVmax value and short-axis diameter of lymph nodes on EBUS. EBUS-TBNA's negative results were followed up radiologically till 6 months to assess the progression, and repeat TBNA was done if there was an increase in size/SUVmax of lymph nodes on follow-up PET/CT thorax. The result of repeat TBNA was considered for the final diagnosis. For the evaluation of diagnostic accuracy, radiological assessment at 6-month follow-up was considered as the gold standard.
PET-CT protocol: Whole body (head to mid-thigh craniocaudal) PET CT scan using Seimens Biograph mCT flow machine was done. Each patient was advised for 6 hours fasting before the scan. Procedure: injection 18 FDG 8-10 intravenously (IV) was given 45 minutes before the scan. Oral contrast (nonionic) 10mL visipaque in 1 L and 50 mL visipaque IV undiluted was given. The scanning was done at 250 mAS and 120 KV. PET slice thickness of 5 mm and CT slice thickness of 3 mm and 5 mm were obtained using 64-slice time-of-flight (TOF) scanner, and PET-CT fusion images were created.
The convex probe EBUS scope BF type UC180F (7.5 MHz. Olympus, Japan) was used for the procedure, a minimum of three passes per node were taken and sampling of nodes was done by 22G/21G ViziShot aspiration needle under real-time imaging guidance.
Cytology and blood clot core were obtained in each case.
Method for obtaining blood clot core: target node was localized by EBUS; TBNA needle assembly was inserted into the channel of the scope and locked while the scope was placed in a neutral position. Once the sheath is visible and the target node is localized, the needle was inserted into the target with a sudden jab. Rapid excursions (15–20) of a minimum of 3–5 mm were performed along with the slow withdrawal of stylet. The negative pressure of 5–6 mL was applied in case if blood clot core is not obtained with the initial pass.
The sedation level was decided on the basis of patient comfort and comorbidities present. Conscious sedation was done by midazolam IV (1–3 mg) for the procedures done in the endoscopy room. Deep sedation/general anesthesia was given by propofol bolus (1 mg/kg) and intravenous infusion (100 mcg/kg/min), fentanyl IV (50–100 mcg), inhalation anesthesia (nitrous oxide, sevoflurane), and vecuronium (100 mcg/kg) IV for procedures done in operation theater with laryngeal mask airway number 4 or endotracheal tube size 8.5 mm.
Sample preparation: samples obtained were dispersed on slides to prepare air-dried and alcohol-fixed smears. Blood clot core obtained was sent into a formaldehyde solution for histopathological evaluation. Immunohistochemical studies were done in undifferentiated tumor/atypical morphology to establish the likely primary.
Granulomatous inflammation: necrotizing (tuberculosis) or non-necrotizing (sarcoidosis) granulomas with supporting investigations such as Mantoux test, acid-fast bacilli staining, serum angiotensin-converting enzyme levels.
Metastasis- when malignant cells were seen on slide smear/blood clot core.
Reactive/normal nodes: no malignant cells, absence of granulomas, presence of lymphocytes only.
Statistical analysis was done using SPSS 17.0 version. Frequency tables, mean, standard deviation, etc., PET-positive. Chi-square test, one-way ANOVA were used. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy were calculated and receiver-operating characteristic (ROC) curve was plotted. This study was approved by the institutional ethics committee (DSCI-IEC/2019-1104).
| » Results|| |
Fifty-seven patients of extrathoracic malignancies underwent the evaluation of PET-positive mediastinal-hilar lymph nodes by EBUS-TBNA. Repeat TBNA was done in six cases based on radiological assessment. Out of 57, 37 were women and 20 were men. The mean age of the patients was 49.32 (range: 21-74) years. The most common extrathoracic malignancy was carcinoma cervix (12 patients), followed by carcinoma breast (11), carcinoma tongue (6), and lymphoma (6). Out of 57 patients, metastasis was diagnosed in 19 (33.3%) patients. Metastasis was detected in five cases of carcinoma breast, four cases of carcinoma larynx, three cases of carcinoma tongue, and two cases of carcinoma prostate and cervix each. Immunohistochemical analysis was done in seven cases.
Total of 74 lymph nodes were sampled. The most common lymph node sampled was subcarinal (30), followed by right lower paratracheal (18), right hilar (9), right upper paratracheal (7), and left hilar (5) patients. The size range of lymph nodes was 8–35 mm, and the SUVmax range was 2.8–18 [Table 1].
Out of 74 sampled nodes, 49 (66.22%) were benign and 25 (33.78%) were malignant. The SUVmax range of benign nodes was 2.8–13 as compared to 3–18 of malignant nodes. The size range of malignant nodes was 8–35 mm and benign nodes was 8–30 mm. [Table 2] The benign lymph nodes were further subdivided into reactive and granulomatous inflammation. There were 32 reactive nodes and 17 nodes reported as granulomatous inflammation. Out of 17 granulomatous nodes, 9 were necrotic and 8 were non-necrotic. The size range of reactive nodes was 8–25 mm, and that of granulomatous nodes was 12–30 mm. The SUVmax range of reactive nodes was 3–13, and that of a granulomatous node was 8–12 [Table 3] and [Figure 1], [Figure 2].
|Figure 1: Distribution of SUVmax (y-axis) of malignant versus reactive vs granulomatous node|
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|Figure 2: Distribution of size of a node: y-axis (short-axis diameter assessed by EBUS) in malignant versus reactive versus granulomatous nodes|
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At SUVmax cut-off 2.5, the positive predictive value and diagnostic accuracy for detecting metastasis was 33.7%. At SUVmax 5.5, diagnostic accuracy increased to 50%, sensitivity and specificity were 72% and 38.7%, respectively. Seven nodes (26.9%) out of 26 will be missed at cut-off 5.5 SUVmax. The sensitivity, specificity, and diagnostic accuracy at SUVmax 7.5 cut-off were 64%, 53.06%, and 56.7%, respectively. False-negative cases were nine at this cut-off, 25.7% of nodes with SUVmax less than 7.5 were malignant [Table 4].
|Table 4: Correlation of SUVmax in predicting metastatic lymph node at various cut-off|
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SUVmax of primary was not known in the majority of the cases hence no correlation could be established between SUVmax of primary and mediastinal lymphadenopathy.
The diagnostic accuracy, sensitivity, and specificity at 10 mm cut-off size were 45.9%, 88%, and 24.9%, respectively, for detecting metastasis. Three (20%) nodes of size less than 10 mm were malignant. At 13.5 mm cut-off, diagnostic accuracy, sensitivity, and specificity were 59.4%, 80%, and 48.9%, respectively, for detecting metastasis. 5 (17.2%) nodes were malignant of size less than 13.5 mm [Table 5].
|Table 5: Correlation of size in predicting metastatic lymph node at various cut-off|
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The mean size of abnormal nodes (metastatic + granulomatous) was 17.5 (8–35 mm), and the mean SUVmax was 9.1 (3.4–18), and it was a statistically significant difference when compared to reactive (normal) nodes. At SUVmax cut-off 7.5, sensitivity, specificity, PPV, and NPV were 78.5%, 81.2%, 84.6%, and 74.2%, respectively for detecting abnormal nodes. At 13 mm size cut-off, sensitivity, specificity, PPV, and NPV were 75.5%, 65%, 75%, and 72%, respectively, for detecting abnormal nodes.
| » Discussion|| |
The common mediastinal lymph nodes involved in extrathoracic malignancies are paratracheal and subcarinal. Subcarinal and paratracheal lymph nodes constitute 74.3% of nodes sampled in our study. Head and neck, carcinoma breast, and genitourinary are the primary malignancies that metastasize to mediastinal lymph nodes., Carcinoma cervix (12 patients) and carcinoma breast (11 patients) are the two most common primary malignancies referred for evaluation of mediastinal nodes in our study, along with head and neck malignancies (11 patients). The incidence of metastasis detected in our study by EBUS-TBNA was 33.3% (19/57 patients). Similar results were obtained in other studies as well.,
The mean SUVmax of malignant nodes and granulomatous nodes was higher than reactive nodes (statistically significant). [Table 3] There are several reasons for false-positivity on PET scan including tuberculosis, sarcoidosis, cryptococcosis, infections, radiation pneumonitis, radiation fibrosis, and granulation tissue. Small size node, bronchoalveolar carcinoma, metastasis of mucinous carcinoma breast, gastrointestinal origin, carcinoid tumors, and low-grade lymphoma are well-documented reasons of false-negative findings on PET scan, making PET scan a poor discriminatory factor in determining metastasis. Granulomatous inflammatory nodes have higher mean SUVmax than malignant and reactive nodes as reported in various studies., Similar results were obtained in our study.
The diagnostic accuracy, sensitivity, and NPV of EBUS-TBNA were 94.7%, 90%, and 90%, respectively in our study. Others reported similarly high accuracy, negative predictive value, and sensitivity of EBUS-TBNA in extrathoracic malignancies.,,
The nodes diagnosed as reactive had a statistically significant lower SUVmax than metastatic nodes and granulomatous nodes. Similar results were noted in other studies. Granulomatous inflammatory nodes are 22.9% in our study, due to which PET scan and ROC curve analysis [Figure 3] failed to show a statistically significant difference between benign versus malignant nodes. The mean size and SUVmax of granulomatous nodes were more than malignant nodes. Granulomatous inflammation is a common phenomenon in neoplastic patients; sarcoid-like reactions, that is, non-necrotizing granulomas in asymptomatic patients do not require any treatment. Sarcoid-like reactions are FDG-avid and important differential diagnosis in patients with hilar/mediastinal lymphadenopathies and a history of malignancy. Steroid treatment is required for associated asthenia. In our study, four patients had non-necrotizing granulomas, and none of them required any treatment, as they were asymptomatic.
|Figure 3: ROC curve analysis of the size and SUVmax of the lymph node in diagnosing metastasis size (AUC-0.643) and SUV (AUC-0.630). ROC: Receiver operating characteristics curve, SUVmax: Maximum standardized uptake value, AUC: Area under the curve|
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Lymph node size, that is, short-axis diameter is widely accepted criteria in discriminating benign from the malignant node. The short-axis diameter is measured perpendicular to the longest diameter of the lymph node, the size threshold varies with the anatomic site.
In a study where different sonographic features were used in predicting metastasis, it was found that at 1 cm cut-off short-axis diameter sensitivity was around 25% and specificity around 95%. At 1.4 cm cut-off, sensitivity and specificity were more than 60%, and diagnostic accuracy was 82.2%. In our study, when 1.5 cm was used as cut-off, sensitivity was 60%, specificity 69.3%, and diagnostic accuracy 66.2%. In our study at 1 cm cut-off, sensitivity was 88%, specificity 24.4%, and diagnostic accuracy 45.9%. We did not find high diagnostic accuracy in predicting metastasis as compared with other studies, as 22% of the nodes in the benign group were granulomatous with mean size more than metastatic node.
In a study conducted in a tuberculosis endemic country, a higher SUVmax cut-off 6.2 was described for differentiating benign versus malignant nodes and comparison between granulomatous nodes (benign) with nodes diagnosed as lymphoma (malignant) was done. Another study quoted SUVmax cut-off 6.3 from ROC analysis to determine metastasis, but only one node was granulomatous in that study. We didn't find a higher SUV cut-off with significant sensitivity and diagnostic accuracy in predicting metastasis.
Since SUVmax even at higher cut-off 7.5 is a poor predictor of metastasis, the diagnostic accuracy of 56.7%, different prediction models are required to improve the test performance of PET-CT. In a study, other parameters such as nodal calcification, the ratio of lymph node SUVmax and ascending aorta SUVmax, superior vena cava SUVmax were assessed. It was found that nodes with nodular calcification were benign, while high lymph node SUVmax and high lymph node/ascending aorta SUVmax were metastatic.
Considering low specificity, diagnostic accuracy, and positive predictive value of size and SUVmax at various cut-off in predicting metastasis as described in our study, there should be a restrictive attitude toward invasive and costly diagnostic testing such as EBUS-TBNA for mediastinal-hilar nodes in extrathoracic malignancies. A higher SUVmax cut-off 7.5 can be considered for differentiating normal/reactive versus abnormal (granulomatous + metastatic) nodes. Granulomatous inflammation is a common differential diagnosis, especially in the tuberculosis endemic region.
The limitations of our study are the non availability of mediastinoscopy that is a gold standard for diagnosis at our institute. We didn't evaluate false-negative nodes on PET scan, as nodes with SUVmax less than 2.5 were not included in the study. The follow-up of 6 months might not be sufficient to confirm false-positive nodes on a PET scan. Detailed morphological characteristics of the node on EBUS-like shape, margin, consistency, necrosis sign, and central hilar sign were not included in this study. Only seven cases of hemopoietic malignancy were available in this series, as hemopoietic malignancies are not routinely treated at our institute. The size mentioned in the PET-CT scan was not compared with the size detected in EBUS. In the majority of cases, lymph node with higher SUVmax was evaluated initially and sampled if feasible as decided by the endoscopist followed by assessment and sampling of other nodes. Sampling and detail morphological evaluation of all the nodes is practically difficult as most of the cases are done in conscious sedation on a daycare basis.
| » Conclusion|| |
The majority of mediastinal-hilar nodes with increased metabolic activity are benign in nature. Size and SUVmax are poor predictors of metastasis in tuberculosis endemic region. There should be a restrictive attitude toward invasive diagnostic testing for mediastinal-hilar nodes in extrathoracic malignancies.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]