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Lymphomatoid Granulomatosis

Radiologic Features and Pathologic Correlations

¹ Department of Radiology, Health Sciences Center, University of Colorado School of Medicine, 4200 E. 9th Ave., Box A030, Denver, CO 80262.
² Present address: Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnar-Dong, Songpa-Ku, Seoul, 138-040 South Korea.
³ Departments of Pathology and Medicine, University of Colorado School of Medicine, Denver, CO 80262.

Received November 8, 1999; accepted after revision April 10, 2000.

 
Address correspondence to D. A. Lynch.

Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
OBJECTIVE. The purpose of this paper is to define the radiologic features of lymphomatoid granulomatosis and correlate them with histopathologic features.

CONCLUSION. Lymphomatoid granulomatosis shows characteristic CT features such as peribronchovascular distribution of nodules, coarse irregular opacities, small thin-walled cysts, and conglomerating small nodules. Large masses and occlusion of large vessels also occur. Histopathologic examination shows the nodules are caused by intravascular and perivascular infiltration by atypical lymphoid cells.

Introduction

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Lymphomatoid granulomatosis, also known as angiocentric lymphoma and angiocentric immunoproliferative lesion, is a complex disease first described by Liebow et al. [1]. Involvement may be unilateral or bilateral and includes interstitial and alveolar compartments of the lung. Progression to lymphoma and high mortality rates have been reported [2, 3]. Lymphomatoid granulomatosis has been recognized as a unique type of extranodal malignant lymphoma on the basis of clinicopathologic, immunophenotypic, and clonal evidence [2, 4,5,6,7,8]. If recognized early, lymphomatoid granulomatosis can be treated. Radiographically, multiple reticulonodular opacities and masses are present in the lung parenchyma [9, 10]. The imaging findings of a series of patients with lymphomatoid granulomatosis have not been described to our knowledge. The purpose of this study was to define the radiologic features of lymphomatoid granulomatosis and correlate them with histopathologic features.

Materials and Methods

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Medical records and chest radiographic, CT, MR imaging, and pathologic findings of five patients with lymphomatoid granulomatosis were retrospectively reviewed. The study group comprised four men and one woman who were 35-83 years old (median age, 51.5 years).

All patients had nonspecific symptoms of pulmonary involvement such as chest discomfort, cough, fatigue, or shortness of breath. One patient presented with an enhancing brain lesion; none of the others had evidence of extrapulmonary involvement. All patients underwent unenhanced helical CT using 7-mm collimation and reconstruction. Three of the five patietns underwent high-resolution CT with 1-mm scans performed at 2-cm intervals. MR imaging was performed on one patient, with axial and coronal gated fast T2-weighted images obtained through the pulmonary vasculature. Two patients had follow-up helical CT. The diagnosis of lymphomatoid granulomatosis was confirmed histopathologically in all patients. The histopathology slides of four patients were available for review.

Common to all cases was the finding of infiltration of the vessel lumen or the subintimal region. Histologically, a well-demarcated, dense mono-nuclear cell infiltrate, prominent vascular infiltration, and foci of necrosis in the cellular infiltrate were the diagnostic features for lymphomatoid granulomatosis. Two radiologists by consensus assessed the presence, appearance, and distribution of parenchymal, mediastinal, and pleural disease on CT scans and chest radiographs.

Results

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Nodules or masses with poorly defined margins were the main findings noted on chest radiographs in all patients. The number of nodules ranged from one to 19. Maximum lesion size ranged from 1 to 5 cm. Cavitation was not found. Linear or reticular abnormality was noted on chest radiographs in two patients.

CT scans of all patients showed well-defined and poorly defined nodules throughout both lungs. The number of nodules ranged from five to more than 60. The diameter of the largest nodule ranged from 1.3 to 6.5 cm; most nodules were smaller than 1 cm.

Nodules were located along the bronchovascular structures or interlobular septa in all patients (Fig. 1). In four patients, a coarse linear pattern occurred along the bronchovascular bundles, coexisting with small nodules and associated with distortion of the architecture of the bronchovascular bundle (Fig. 1). Histopathologic examination revealed that these nodules were caused by pulmonary vascular involvement by a variable number of small and large lymphoid cells. The peribronchovascular and interstitial distribution of the lesions reflected the tendency of the lymphomononuclear cells to infiltrate the subintimal region of medium-sized arteries and veins. Thin-walled cystic lesions (size range, 1-2 cm) were noted in three patients (Fig. 2). Mediastinal lymphadenopathy was noted in three patients.

View larger version (114K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1. —35-year-old man who presented with cerebral symptoms with enhancing brain mass on CT. CT image shows well-defined and poorly defined nodules throughout lung. Most nodules are smaller than 1 cm. Nodules are located along bronchovascular structures or interlobular septa.

View larger version (106K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —59-year-old man who presented with abnormal findings on chest radiography. CT image at level of lung apex shows several small thin-walled cysts, 1-2 cm in diameter. Histopathology revealed extensive confluent coagulative necrosis, often with presence of pulmonary vessels infiltrated by lymphoma. Areas of necrosis were surrounded by lymphoepithelioid infiltrate with focal formation of poorly formed granulomas.

Two patients showed large masses (>5 cm) and had follow-up CT after treatment. Follow-up information was not available for the other patients. One patient had a mass in the lingular segment of the left upper lobe. After treatment with melphalan and prednisone, the mass decreased in size, but multiple smaller nodules appeared that showed central low-density areas (Fig. 3A,3B,3C,3D,3E,3F). At histopathologic examination of this patient, the central low-density areas represented large areas of extensive confluent coagulative necrosis. In the preserved areas, there was an infiltrate of lymphoid cells surrounding and invading vascular structures.

View larger version (211K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A. —83-year-old man who presented with left upper lobe mass on chest radiography. v = vascular lumen. Photomicrograph of mediumsized pulmonary artery shows infiltration of intima and subintima (arrow) by intense lymphomononuclear infiltrate, resulting in destruction of vascular wall. Note reduced vascular lumen. (H and E, x200)

View larger version (206K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B. —83-year-old man who presented with left upper lobe mass on chest radiography. v = vascular lumen. High-magnification photomicrograph shows atypical lymphomononuclear cell infiltrate composed predominantly of large cells infiltrating vascular wall seen in A. (H and E, x600)

View larger version (192K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3C. —83-year-old man who presented with left upper lobe mass on chest radiography. v = vascular lumen. Photomicrograph of B-cell (CD20)—labeled tissue shows that malignant cells react predominantly with B-cell marker. (x400)

View larger version (205K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3D. —83-year-old man who presented with left upper lobe mass on chest radiography. v = vascular lumen. Photomicrograph of CD3-labeled cells shows only patchy reactivity with this T-cell marker.

View larger version (184K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3E. —83-year-old man who presented with left upper lobe mass on chest radiography. v = vascular lumen. Photomicrograph of cells labeled by in situ hybridization for Epstein-Barr virus shows that malignant lymphocytes exhibit Epstein-Barr virus DNA (arrows). (x600)

View larger version (117K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3F. —83-year-old man who presented with left upper lobe mass on chest radiography. v = vascular lumen. CT image at level of right upper lobar bronchus shows mass in posterior segment of right upper lobe coexisting with bilateral small nodules. Architecture of bronchovascular bundle of left upper lobe is distorted.

The second patient had large conglomerate masses with air bronchograms. In this patient, numerous small aggregated nodules formed well-defined irregularly marginated nodules of variable size (Fig. 4A). After treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone for 6 months, the nodules and masses markedly decreased in size and almost disappeared. However, coarse linear opacities along bronchovascular bundles became more abundant (Fig. 4B).

View larger version (88K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A. —48-year-old woman who presented with hypercalcemia and multiple pulmonary nodules. CT image reveals multiple large conglomerated masses with air bronchogram. Numerous small nodules have aggregated to form well-defined irregularly marginated nodules of variable size.

View larger version (97K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B. —48-year-old woman who presented with hypercalcemia and multiple pulmonary nodules. CT image at same level as A, obtained after patient underwent treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone for 6 months, reveals nodules and masses are smaller and have almost disappeared. However, coarse linear opacities along bronchovascular bundle have become more abundant.

In one patient, MR images revealed several masses (Fig. 5A,5B) in the peripheral lung parenchyma and perihilar area. The masses showed higher signal intensity than muscle on T1- and T2-weighted images. The right upper lobe pulmonary artery was narrowed by the perihilar mass. Severe thickening of the wall of the left main pulmonary artery was noted, with complete occlusion by thrombosis or tumor. At histopathologic examination, infiltration by atypical lymphocytes was noted predominantly in the wall of the pulmonary artery. Consolidation in the left lower lobe of this patient was thought to be caused by pulmonary infarction.

View larger version (92K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5A. —42-year-old woman with pulmonary arterial occlusion caused by lymphomatoid granulomatosis. T1-weighted MR axial image at level of right main pulmonary artery shows several irregular nodules in peripheral lung parenchyma. Mass or thrombus is noted in right pulmonary artery, extending into lumen of main pulmonary artery (arrow). Descending left pulmonary artery is occluded.

View larger version (111K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5B. —42-year-old woman with pulmonary arterial occlusion caused by lymphomatoid granulomatosis. T1-weighted MR sagittal image through left main pulmonary artery shows severe thickening of artery wall (arrows), with complete occlusion of artery by thrombosis or tumor. Note left suprahilar mass (arrowhead).

Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Since the original description by Liebow et al. [1], pathologists have recognized lymphomatoid granulomatosis on the basis of its distinctive pulmonary lesions containing polymorphous and atypical lymphoreticular infiltrate with striking involvement of vessels and variable necrosis. Debate continues as to whether lymphomatoid granulomatosis is a primary vasculitis or whether it should be classified in the clinicopathologic spectrum of malignant lymphoma [6, 7]. Clinicopathologic studies have shown that progression of lymphomatoid granulomatosis to lymphoma occurs in 12-47% of patients, and the mortality rate has been reported to be between 53% and 63.5% [2, 3].

Small monomorphic foci resembling malignant lymphoma have been found in many cases of lymphomatoid granulomatosis, and repeated biopsies from the same patients over time have revealed progressive emergence of atypical lymphoid cells and eventual evolution to relatively monomorphous malignant lymphoma [6, 11]. Initial immunohistochemical studies of frozen sections showed that most cells in these lymphomatoid granulomatosis lesions were T cells [5]. Katzenstein and Peiper [12] subsequently identified Epstein-Barr virus by polymerase chain reaction in most cases of lymphomatoid granulomatosis, implicating that virus in the pathogenesis of this disorder. More recently, combined immunohistochemistry and in situ hybridization confirmed the presence of Epstein-Barr virus sequences in B cells and the absence of Epstein-Barr virus in T cells [7]. Most cases of lymphomatoid granulomatosis involving the lung represent a proliferation of Epstein-Barr virus-infected B cells with a prominent T-cell reaction and vasculitis [7].

Depending on the relative proportions of atypical cells and inflammation, lymphomatoid granulomatosis can be graded from 1 (least atypia) to 3 (greatest atypia). Most investigators now believe that lymphomatoid granulomatosis, particularly grades 2 and 3 lesions, are probably malignant. Because of the proliferation of B cells, lymphomatoid granulomatosis differs from angiocentric T-cell lymphoma in other sites, such as the head and neck [4, 6, 8, 11].

Dee et al. [9] described two distinct radiographic manifestations of lymphomatoid granulomatosis. In their series, diffuse reticulonodular opacities correlated microscopically with angiocentric granulomatous infiltration without pulmonary infarction, whereas larger masslike opacities corresponded to biopsyproven pulmonary infarcts within lymphomatoid granulomatosis lesions. Our study similarly found that central areas of low density were correlated with areas of necrosis. However, in our study, central necrosis also occurred in nodules smaller than 2 cm. In the preserved nonnecrotic areas, an infiltrate of lymphoid cells surrounded and invaded vascular structures. This infiltration may cause the central necrosis.

Hicken et al. [10] found that lung nodules are the most common feature in lymphomatoid granulomatosis, occurring in perhaps 80% of cases, and cavitation was noted in five of 24 patients in their study. In our series, pulmonary nodules were the most common findings and were noted in all five patients on CT images. The margins of the nodules were irregular, but well-defined, in all but one patient. The nodules were distributed along the bronchovascular bundles or interlobular septa. This distribution can be explained by the angiocentric distribution of lymphomatoid granulomatosis. Small thin-walled cystic lesions were noted in three patients. We could not determine if these cystic lesions were true cavities resulting from central necrosis of nodules.

One of our patients had a mass growing through the lumen of the pulmonary artery with vascular occlusion. To our knowledge, this finding has not previously been described. MR imaging or contrast-enhanced CT in patients with lymphomatoid granulomatosis who have hilar masses may help determine the presence and extent of arterial narrowing or occlusion.

The radiologic differential diagnosis for lymphomatoid granulomatosis is long and includes pseudolymphoma, malignant lymphoma, lymphocytic interstitial pneumonia, metastasis, sarcoidosis, Wegener's granulomatosis, and cryptogenic organizing pneumonia. These conditions could not be distinguished radiologically from lymphomatoid granulomatosis on the basis of our study findings.

Lymphomatoid granulomatosis involves the skin in about 33% of cases and the brain in about 20% [13], as was seen in one of our patients. The CT appearance of cerebral involvement is diverse. The disease is most commonly seen as low-attenuation areas in the white matter, is sometimes hemorrhagic, and often enhances with IV contrast material. The lesions may be perivascular [14].

Even though it is unlikely that such a rare condition could reasonably be diagnosed on the basis of the radiologic features alone, lymphomatoid granulomatosis shows characteristic CT features such as peribronchovascular distribution of nodules and coarse irregular opacities, small thinwalled cysts, and conglomerating small nodules.

References

Top Abstract Introduction Materials and Methods Results Discussion References

 

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