Radial Endobronchial Ultrasound to Diagnose a Case of Non-Hodgkin’s Lymphoma in the Lung: A Case Report and Literature Review

Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of lymphoproliferative malignancies that are very rarely seen in the lung. Although they generally have a favorable prognosis, the clinical symptoms and most efficient methods of diagnosis have not yet been clearly defined. This report highlights an interesting case wherein a 75-year-old male who presented with complaints of fever, cough, and generalized weakness for three weeks was diagnosed and treated as a case of pneumonia. He did not respond to conventional treatment with antibiotics and antipyretics. Hence, computed tomography of the thorax was done which showed consolidation in the right lower lobe along with a few enlarged right hilar nodes. To evaluate this unresolved pneumonia, he was further evaluated with a radial endobronchial ultrasound (EBUS) and biopsy, which helped in arriving at a diagnosis of NHL. This case illustrates the significance of advanced interventions such as radial EBUS to identify the exact etiology of the lesions. This is the first case to document the ultrasound images of NHL in the lung, obtained using a radial EBUS.


Introduction
Most patients with non-Hodgkin's lymphoma (NHL) of the lung are asymptomatic and are diagnosed following routine X-ray screenings, showing infiltrates in the lung.However, if symptoms are present, they are most commonly non-specific and include fever, weight loss, and night sweats.Respiratory symptoms, if present, include cough, pain or pressure sensation in the chest, or dyspnea [1].Due to this non-specific presentation, arriving at a diagnosis of NHL in the lung may be missed in a large proportion of patients.Xrays generally show pulmonary abnormalities resembling pneumonia, such as consolidation with air bronchograms.As a result, patients with NHL who are treated as pneumonia see no improvement in their symptoms or X-rays [2].
A thorough evaluation of suspected cases should include computed tomography (CT) of the thorax to assess and identify potential hilar and mediastinal lymphadenopathy which may prompt further investigation to support the diagnosis of NHL.Radial-probe endobronchial ultrasound (EBUS) has emerged as a widely accepted procedure that can help localize and guide tissue sampling for an accurate diagnosis of peripheral pulmonary nodules [3,4].Here, we discuss an interesting case of NHL in the lung which presented as a classic case of pneumonia.Due to the unresolved nature even after treatment with antibiotics, we took the patient up for radial EBUS with biopsy to arrive at an accurate diagnosis.

Case Presentation
A 75-year-old man with no comorbidities was hospitalized with fever, cough, and loss of weight and appetite for three weeks.Physical examination was significant for a temperature of 100.2°F, normal vesicular breath sounds with bronchial breath sounds in the right infrascapular region, no superficial lymph nodes, and oxygen saturation of 95% in room air.Chest X-ray revealed consolidation in the right lower zone, as demonstrated in Figure 1, Panel A. A provisional diagnosis of right pneumonia was made.He was treated with a course of antibiotics (intravenous ceftriaxone and oral macrolides) for 10 days, despite which the symptoms persisted, leading to further investigations.The sputum examination was negative for acid-fast bacilli, and Mycobacterium tuberculosis was not detected in GeneXpert MTB/RIF assay.CT of the thorax revealed a consolidation in the right lower lobe along with a few areas in the right upper lobe (Figure 1, Panel B).Mild heterogenous enhancement of the consolidation was noted, and there was no evidence of necrosis.There were a few enlarged right hilar lymph nodes, with the largest measuring 11 mm in short axis.Histology was suggestive of NHL and immunohistochemistry markers were sent for further subtyping which showed that leukocyte common antigen was diffusely positive, CD3 was reactive, and CD20 diffusely positive.This helped in confirming our diagnosis of NHL of B-cell origin.A positron emission tomography (PET) scan showed metabolically active lesions in the right upper and lower lobes of the lung, as well as involvement in the subcarinal, paraesophageal lymph nodes, and spleen, helping to confirm the staging as stage III lymphoma.

Discussion
Primary NHL of the lung is an uncommon condition, accounting for only 0.4% of all lymphomas, in contrast with secondary lung involvement, which is more prevalent in individuals with a lymphoma history (incidence 25% to 40%) [1].Two studies by Ferraro et al. and Li et al. showed that out of 92 NHL patients, 43.4% (40 patients) were asymptomatic and diagnosed only after routine radiography, while the remaining 56.5% (52 patients) had either systemic or respiratory symptoms, most commonly fever, weight loss, night sweats, dyspnea, and cough [1,2].Our patient had unresolved cough, breathlessness, and fever for 22 days, despite treatment with antibiotics and other supportive medications, due to which we opted to biopsy the lesion using radial EBUS as a navigation tool.Radial-probe EBUS can precisely locate peripheral pulmonary nodules or masses and allows for clear visualization of bronchial and vascular structures, reducing the incidence of complications such as bleeding, while avoiding areas of necrosis to improve diagnostic yield [3,4].Kurimoto et al. [5] classified EBUS patterns into three distinct categories with six subsets, as shown in Table 1.

Classification Characteristics Etiology
Type  Chao et al. suggested that four distinct sonographic features (lobulation, margins, blood vessels, and air bronchogram) can help determine whether a lesion is benign or malignant [6].In our case, radial EBUS showed hyperechoic dots and a linear arc pattern with blood vessels (Type IIb).
Extranodal lymphomas in the lung are rare (usually low-grade B-cell types) and originate from mucosaassociated lymphoid tissue from the bronchus [7].Histopathological analysis of the biopsied sample in our case showed an endobronchial lesion composed of monomorphic medium-to-large atypical lymphoid cells with oval-to-round nuclei with fine chromatin.CD20 was positive in the atypical lymphoid cells and CD3 showed a reactive pattern.Based on the above findings, a diagnosis of diffuse large B-cell lymphoma (DLBCL) type of NHL was given.
Treatment of NHL commonly involves a combination of chemotherapy, radiotherapy, and immunotherapy and is based on the stage and tumor burden.Monoclonal therapy and radioimmunoconjugate therapy have become the standard of care for the treatment of indolent lymphomas, while aggressive lymphomas are generally treated using either the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-CHOP regimen [8].Rituximab (anti-CD20 agent)-based chemotherapy regimens have shown very favorable outcomes in patients with DLBCL [9,10].Anthracyclines such as doxorubicin have been associated with increased incidence of dose-related cardiotoxicity due to myocarditis, due to which in our institute we initiate chemotherapy with the RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and oral prednisolone) regimen [11].Our patient was successfully treated with a total of six cycles of the RCEOP regimen which yielded a favorable outcome with significant symptomatic improvement and repeat PET showed a reduction in metabolically active lesions.

Conclusions
NHL of the lung is a very rare condition, often presenting with non-specific symptoms that can lead to delayed diagnosis and treatment.Our recent case underscores the crucial role of radial EBUS as a pivotal tool in obtaining a biopsy sample in a patient.Its ability to provide real-time imaging guidance during bronchoscopic procedures offers clinicians a minimally invasive and precise means to sample suspicious lesions within the lung parenchyma.By facilitating accurate tissue acquisition, EBUS enhances diagnostic yield and ultimately guides treatment strategies for patients.The utility of radial EBUS not only lies in its diagnostic efficacy but also in its potential to minimize procedural risks and expedite patient management, thus underscoring its indispensable role in the multidisciplinary approach to managing NHL of the lung.

FIGURE 1 :
FIGURE 1: (A) Chest X-ray showing consolidation in the right lower lobe (arrow).(B) High-resolution CT of the thorax demonstrating evidence of subpleural and peribronchial consolidation in the right lower lobe (arrow).(C) R-EBUS image demonstrating central hypoechoic mass with linear arcs and dots within the lesion (arrow), surrounded by a hyperechoic margin, thus confirming R-EBUS within the lesion.CT: computed tomography; R-EBUS: radial endobronchial ultrasound

FIGURE 2 :
FIGURE 2: Endobronchial tissue fragments lined by ciliated columnar epithelium with underlying stroma consisting of monomorphic sheets of medium-to-large atypical lymphoid cells with round-to-oval vesicular nuclei with prominent nucleoli traversed by fibrovascular strands, atypical mitoses seen with no evidence necrosis.Staining agent used: hematoxylin and eosin (A).Atypical lymphoid cells which are diffusely positive for Immunohistochemistry marker CD20 (magnification ×40) (B).