ABSTRACT

Objective: Evaluation of enlarged mediastinal lymph nodes is crucial for patient management. Malignant lymphoma and sarcoidosis are often difficult to differentiate. Our objective was to determine the diagnostic accuracy of MRI for differentiating between sarcoidosis and malignant lymphoma. Methods: This was a retrospective study involving 47 patients who underwent chest MRI and were diagnosed with one of the diseases between 2017 and 2019. T1, T2, and diffusion-weighted signal intensity were measured. Apparent diffusion coefficients (ADCs) and T2 ratios were calculated. The diagnostic performance of MRI was determined by ROC analysis. Results: Mean T2 ratio was significantly lower in the sarcoidosis group than in the lymphoma group (p = 0.009). The T2-ratio cutoff value that best differentiated between lymphoma-related and sarcoidosis-related enlarged lymph nodes was 7.1, with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 58.3%, 95.6%, 76.5%, 93.3%, and 68.7%, respectively. The mean ADC was significantly lower in the lymphoma group than in the sarcoidosis group (p = 0.002). The ADC cutoff value that best differentiated between lymphoma-related and sarcoidosis-related enlarged lymph nodes was 1.205, with a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 87.5%, 82.6%, 85.1%, 84.0% and 86.3%, respectively. No significant differences were found between the two groups regarding T1 signal intensity, T2 signal intensity, and lymph node diameter. Conclusions: MRI parameters such as ADC, diffusion, and T2 ratio can be useful in the differentiation between sarcoidosis and lymphoma in the evaluation of enlarged lymph nodes.

Keywords: Diffusion magnetic resonance imaging; Lymphoma; Lymph nodes; Sarcoidosis.

RESUMO

Objetivo: A avaliação de linfonodomegalias mediastinais é crucial para o manejo dos pacientes. O linfoma maligno e a sarcoidose costumam ser difíceis de diferenciar. Nosso objetivo foi determinar a precisão diagnóstica da RMN para diferenciar sarcoidose de linfoma maligno. Métodos: Estudo retrospectivo com 47 pacientes submetidos a RMN de tórax e diagnosticados com uma das doenças entre 2017 e 2019. Foi medida a intensidade do sinal em T1, T2 e difusão. Foram calculados o coeficiente de difusão aparente (ADC, do inglês apparent diffusion coefficient) e a razão T2. O desempenho diagnóstico da RMN foi determinado pela análise da curva ROC. Resultados: A média da razão T2 foi significativamente menor no grupo sarcoidose que no grupo linfoma (p = 0,009). A razão T2 = 7,1 foi o melhor valor de corte para diferenciar linfonodomegalias relacionadas com linfoma daquelas relacionadas com sarcoidose, com sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e precisão de 58,3%, 95,6%, 76,5%, 93,3% e 68,7%, respectivamente. A média do ADC foi significativamente menor no grupo linfoma que no grupo sarcoidose (p = 0,002). O ADC = 1,205 foi o melhor valor de corte para diferenciar linfonodomegalias relacionadas com linfoma daquelas relacionadas com sarcoidose, com sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e precisão de 87,5%, 82,6%, 85,1%, 84,0% e 86,3%, respectivamente. Não houve diferença significativa entre os grupos quanto à intensidade do sinal em T1, intensidade do sinal em T2 e diâmetro dos linfonodos. Conclusões: Parâmetros de RMN como ADC, difusão e razão T2 podem ser úteis na diferenciação entre sarcoidose e linfoma na avaliação de linfonodomegalias.

Palavras-chave: Imagem de difusão por ressonância magnética; Linfoma; Linfonodos; Sarcoidose.

INTRODUCTION
 
The evaluation of mediastinal lymph nodes is clinically essential for effective disease management and accurate prognosis.(1) Various infectious, inflammatory, and malignant conditions can cause mediastinal lymph node enlargement. Sarcoidosis is a benign systemic disorder of unknown etiology that frequently underlies thoracic diseases, chest abnormalities being seen in 85-95% of the patients who undergo chest X-ray.(2) In contrast, lymphoma is a malignant tumor of the lymphatic system that arises in lymphocytes. Interestingly, not only do these two conditions affect the lymph nodes, but the age at onset of both also overlaps. As such, the adenopathy caused by lymphoma can be confused with sarcoidosis upon initial detection even after imaging.(3)
 
When mediastinal lymph node enlargement occurs, histopathological analysis is the recommended means of obtaining a definitive diagnosis, providing a prognosis and determining which treatment course is best suited to manage the disease. However, interventional access to the mediastinum entails inherent risks for patients and sampling error. It also places a psychological burden on the patient during the period between the detection of the adenopathy by imaging methods and sampling results. Imaging techniques are very efficient in locating and evaluating enlarged mediastinal nodes.(4-6)
 
A readily available, primary technique for evaluating thoracic diseases is CT imaging. Despite being a well-established technique for pulmonary evaluation when used to assess lymph nodes, CT relies on morphological characteristics such as location, size, and distribution of lymph nodes. Cases of sarcoidosis with atypical findings and uncertain diagnosis can mimic other pathologies; the appearance of lymph nodes on CT scans can even resemble malignant disease.(7,8) Thus, the use of CT imaging is limited when it comes to distinguishing between malignant and benign enlarged lymph nodes. (7,9-12) PET-CT, a metabolic imaging technique, has promising yet controversial diagnostic potential for differentiation between granulomatous and malignant disease.(13,14) Although PET-CT is helpful for detecting malignant disease, it is more expensive, less accessible, and lacks specificity when compared with traditional CT.(15,16) In this scenario, MRI is a radiation-free, highly reproducible technique that is well-suited for lymph node assessment. (17) The lack of ionizing radiation makes it particularly appealing for evaluating young adults with symptoms that merely resemble malignancy. MRI sequences, such as diffusion-weighted imaging (DWI), can also provide quantitative metrics that facilitate effective lymph node characterization.(18-24)
 
The purpose of the present study was to determine the diagnostic accuracy of MRI for differentiating between sarcoidosis and lymphoma by quantitative evaluation of mediastinal lymph nodes in patients with either condition.
 
METHODS
 
Our institutional review board approved this study. Patient consent was waived due to the retrospective nature of the study. The authors have no conflicts of interest to declare.
 
Study population
 
This retrospective study included 47 consecutive adult patients from our institution who underwent chest MRI and were histopathologically diagnosed with either sarcoidosis or lymphoma over the course of two years (between January of 2017 and January of 2019). The diagnosis of sarcoidosis was based on the three major criteria recommended by the American Thoracic Society(25): compatible clinical presentation, exclusion of alternative causes of granulomatous nodules, and histopathological evidence of non-necrotizing granulomatous inflammation. Patients whose MRI assessment was performed after treatment initiation were excluded from the analysis. Patients with recent thoracic interventions, radiation therapy initiated prior to MRI acquisition, or an active concomitant infectious disease were also excluded. Clinical data were obtained from the electronic medical records of the patients (Tasy EMR, Philips Clinical Informatics, Blumenau, Brazil).
 
MRI protocol
 
MRI was performed using a 1.5-T scanner (Magnetom AERA; Siemens Healthineers, Erlangen, Germany). A dedicated 8-element integrated matrix coil system covering the entire thorax was used for signal reception. A half-Fourier acquisition single-shot turbo spin-echo sequence was used. The following sequence parameters were used: repetition time (TR)/echo time (TE)/flip angle, infinite/92 ms/150°; parallel acquisition factor, 2; slice thickness, 5 mm; distance factor, 20%; and matrix size, 380 × 256 mm (transversally) and 400 × 320 mm (coronally). A volumetric interpolated breath-hold examination (VIBE) sequence was chosen for fast T1-weighted MRI. For the VIBE sequence, imaging parameters were as follows: TR/TE, 5.12 ms/2.51 ms; flip angle, 10°; partition thickness, 5 mm with no interslice gap; and matrix size, 256 × 116 mm, with a three-dimensional breath-hold imaging technique. A T2-weighted fat-saturated periodically rotated overlapping parallel lines with enhanced reconstruction sequence (BLADE; Siemens Healthineers) was also used, imaging parameters being as follows: TR/TE, 4,670 ms/113 ms; and partition thickness, 5 mm with no interslice gap. DWI was performed using a single-shot echo-planar technique, with a slice thickness of 6 mm under spectral attenuated inversion recovery and respiratory-triggered scanning. DWI parameters were as follows: TR/TE/flip angle, 3,000-4,500 ms/65 ms/90°; diffusion gradient encoding in three orthogonal directions; b = 0 and 800 s/mm2; field of view, 350 mm; and matrix size, 128 × 128 mm. Imaging parameters are summarized in Table 1.

 
Image analysis
 
The MRI files were independently reviewed by two subspecialized chest radiologists who were blinded to patient clinical information and final diagnoses. When differences of opinion arose between the radiologists, a consensus was reached.
 
The largest lymph node from each patient was visually selected by the radiologist on the T2-weighted image. An elliptical two-dimensional region of interest was drawn around the chosen lymph node area on T2-weighted, T1-weighted, DWI, and apparent diffusion coefficient (ADC) map reconstructions. Necrotic regions were avoided. An elliptical region of interest was also placed around the adjacent latissimus dorsi muscle for T2-ratio determination. The T2 ratio was calculated by the signal intensity of the lymph node (ST2 lymph node) divided by the signal intensity of the latissimus dorsi muscle (ST2 skeletal muscle) on a T2-weighted image (i.e., T2 ratio = ST2 lymph node/ST2 skeletal muscle). Lymph node location, dimensions, and signal intensity (T1, T2, and diffusion-weighted signal intensity), as well as ADC, were recorded.
 
Statistical analysis
 
The data are presented as frequency and proportion, mean ± SD, or median [IQR]. The relationships between categorical variables were assessed using chi-square tests. To compare continuous variables, the Student’s t-test or the unequal variance t-test was used. Sensitivity, specificity, positive predictive value, and negative predictive value of the MRI findings were calculated in relation to the corresponding histopathological diagnosis. Kappa coefficients were calculated to determine the inter-rater agreement using a 2 × 2 contingency table. A 95% CI was used. In all cases, the level of statistical significance was set at p < 0.05. All statistical analyses were performed using the IBM SPSS Statistics software package, version 22.0 (IBM Corporation, Armonk, NY, USA).
 
RESULTS
 
A total of 51 consecutive patients were initially included in the study. Three patients were excluded because they initiated treatment prior to undergoing MRI. One patient with a previous diagnosis of sarcoidosis was excluded because he eventually had a definitive diagnosis of tuberculosis. The remaining 47 patients with histopathology-based diagnoses of sarcoidosis or lymphoma were included in the study. A flow chart of the patient selection process is depicted in Figure 1. In our sample, 27 patients (57%) were men. The mean age of the patients was 51 ± 17 years. All of the patients were biopsied via mediastinoscopy. Of the 47 included patients, 23 (47%) had sarcoidosis and 24 (53%) had lymphoma. In the lymphoma group, 20 patients had non-Hodgkin’s B-cell lymphoma and 4 had nodular sclerosing Hodgkin’s lymphoma.

 
The mean diameters (including both short and long axis diameters) were 1.62 ± 0.60 cm in the sarcoidosis group and 2.78 ± 0.83 cm in the lymphoma group. In the sarcoidosis group, the largest lymph nodes were located in the subcarinal (n = 19) and right paratracheal (n = 4) spaces. In the lymphoma group, the largest lymph nodes were found in the subcarinal (n = 20), right hilar (n = 2), left paratracheal (n = 1), and left hilar (n = 1) spaces. Of the 23 patients with sarcoidosis, 20 had typical parenchymal CT findings of interstitial micronodules.(26) One patient exhibited pulmonary fibrosis, and 2 patients presented with no signs of pulmonary disease.
 
There were no significant differences between the two groups in terms of T1 signal intensity, T2 signal intensity, lymph node location, or lymph node size. The mean T2 ratio was significantly lower in the sarcoidosis group than in the lymphoma group (5.0 [3.7-5.3] and 8.3 [4.9-11.9], respectively; p = 0.009), as was the mean diffusion of the lymph nodes (22 [19-54] and 58 [24-96], respectively; p = 0.003). The mean ADC was significantly lower in the lymphoma group than in the sarcoidosis group (0.993 ± 0.508 × 10−3 mm2/s vs. 1.668 ± 0.732 × 10−3 mm2/s; p = 0.002). A ROC curve indicated that an ADC cutoff value of 1.205 × 10−3 mm2/s was optimal for differentiating between lymph nodes affected by lymphoma and those affected by sarcoidosis. Using this cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 87.5%, 82.6%, 85.1%, 84.0%, and 86.3%, respectively. The T2 ratio cutoff value that best differentiated between lymphoma-affected and sarcoidosis-affected lymph nodes was 7.1, with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 58.3%, 95.6%, 76.5%, 93.3%, and 68.7%, respectively. A kappa coefficient of 0.69 reflected substantial inter-rater agreement. A comprehensive comparison of the MRI findings between the sarcoidosis and lymphoma groups is shown in Table 2. Figures 2 and 3 exemplify our findings.

 


DISCUSSION
 
Given that pulmonary sarcoidosis can mimic several other pathologies, including malignant causes of adenopathy,(8) the differentiation between sarcoidosis and such pathologies is crucial for ensuring optimal patient outcomes. The importance of precise imaging-based diagnoses has motivated extensive research on more specific and sensitive means of determining the causes underlying lymph node enlargement. Mehrian & Ebrahimzadeh(12) used CT scans in order to identify variations in the site and morphology of thoracic lymph nodes that correlated differentially with sarcoidosis and lymphoma. Koo et al.(14) demonstrated that there was no significant difference between lymph nodes affected by sarcoidosis or malignant lymphoma using PET-CT, reinforcing the similarity between these pathologies and the difficulty of reaching a definitive diagnosis even with advanced imaging techniques. In the present study, MRI evaluation illuminated characteristics of enlarged mediastinal lymph nodes that have reliably and reproducibly distinguished between sarcoidosis and lymphoma.
 
Previous studies have also used MRI to differentiate between malignant and benign lymph node pathologies successfully using DWI- and ADC-based quantitative measurements.(18-24) Diffusion evinces the mobility of water molecules within tissues. Cellularity is a common pathological feature that is characteristic of neoplasms, restricting the movement of water molecules and thereby reducing their diffusion. However, lymph node enlargement caused by benign diseases (e.g., infection, congestive heart failure, and drug-induced lymphadenopathy) is more likely to increase diffusion. Due to the aforementioned characteristic of cellularity, MRI is not effective in differentiating subtypes of neoplasms. For example, Matoba et al.(27) found that the ADC values of lymph nodes affected by metastatic small cell carcinomas were not significantly different than those of lymph nodes affected by non-small cell carcinomas. Our results confirmed that ADC values of lymph nodes affected by malignant lymphoma were significantly lower than those of lymph nodes affected by sarcoidosis. Diffusion measurements also differed significantly, with lower values in the sarcoidosis group than in the malignant lymphoma group. The findings of the present study support the use of DWI and ADC mapping as an effective and accurate resource for distinguishing between mediastinal lymph nodes affected by either malignant or benign diseases.
 
Only patients who underwent MRI prior to initiating treatment were included in the present study, because the impact of treatment on DWI findings remains undetermined. Lymph node size and cellularity could change upon therapeutic intervention, as could tumor size and ADC values. One study(28) used DWI to evaluate lymph node eradication after chemoradiation therapy in patients with locally advanced rectal cancer, but no additional diagnostic benefit was conferred by adding DWI to the T2 imaging findings. In contrast, another study(29) found that DWI is more accurate than CT when assessing response to radiation therapy, chemotherapy, or both.
 
An important finding from this study is that the T2 ratio is lower in sarcoidosis-affected lymph nodes than in lymphoma-affected lymph nodes. The use of T2 ratio in our study is justified to avoid interindividual differences, such as those frequently caused by receiver-coil bias. The correlation between fibrotic and calcified contents in sarcoidosis-related lymph node enlargement is likely to be the cause of the lower T2 ratio found in our study, which aligns with the aforementioned literature. The T2 ratio was more specific but less accurate than ADC values in differentiating between mediastinal lymph nodes enlarged due to either lymphoma or sarcoidosis.
 
Chung et al.(30) described the dark lymph node sign, an MRI finding that is characteristic of lymph nodes affected by sarcoidosis. A possible correlation with fibrotic content may underlie the dark lymph node sign—a node with low internal intensity and hyperintensity along the peripheral rim on T2-weighted imaging. That study,(30) however, did not include patients with malignant diseases, such as lymphoma, which restricts their findings to granulomatous diseases. Moreover, they did not measure the signal intensity and based their findings on a largely qualitative evaluation of the imaging examination.
 
Our study has some limitations. The retrospective nature of the study carries inherent selection biases, and the data obtained from the electronic medical records of the patients could potentially be inaccurate, which could affect our results. Another limitation was the small number of patients with atypical findings of sarcoidosis on MRI imaging. Although no patients had active tuberculosis infection, the subjects were recruited from a population highly affected by the disease. Any selection bias in our research criteria could have prevented the inclusion of patients during the study period if the terms lymph nodes, sarcoidosis, or lymphoma were not cited in the medical reports. Although we controlled the MRI evaluation performed by the radiologists by using quantitative measurement parameters, another limitation is the inter-rater variability regarding the selection of the largest lymph node, lymph node measurements, and MRI signal quantification. Future studies should include cases of patients with enlarged mediastinal lymph nodes caused by other conditions (e.g., metastases, infectious diseases, and other inflammatory conditions). Quantitative evaluation of enlarged lymph nodes due to diseases other than sarcoidosis and lymphoma represents an important addition to the understanding of the behavior of lymphadenopathies within the context of different thoracic diseases.
 
In conclusion, MRI-based indications of diffusion and T2 ratio can facilitate the differentiation between sarcoidosis-related and lymphoma-related enlarged mediastinal lymph nodes. Although the T2 ratio was more specific but less accurate than ADC values, their combined ability to make such a crucial clinical distinction using MRI data represents an invaluable diagnostic advancement that is particularly relevant for young patients presenting with sarcoidosis or lymphoma, whose symptoms are highly similar.
 
AUTHOR CONTRIBUTIONS
 
FSS and BH: study conception and design, literature search, and acquisition and interpretation of data; GW: statistical analyses; FSS, GW, TMM, and THM: drafting of the manuscript; BH, EM, NV, THM, and TMM: critical revision of the manuscript for important intellectual content; BH: supervision, data integrity, and guarantor of the article.

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