Lymphomatoid Granulomatosis

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Background

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus–associated systemic angiodestructive lymphoproliferative disease. It is characterized by prominent pulmonary involvement but can also involve multiple extrapulmonary sites.

Originally described among diseases characterized by pulmonary angiitis and granulomatosis, it mimics Wegener granulomatosis (WG) both clinically and radiographically. However, recent advances have characterized lymphomatoid granulomatosis as a B-cell lymphoma and have provided etiologic insights that may lead to therapeutic advances.

Pathophysiology

The pathogenesis of lymphomatoid granulomatosis is unknown; however, recent studies have provided overwhelming evidence that lymphomatoid granulomatosis is a distinctive type of malignant lymphoma associated with immunosuppression.[1]

Lymphomatoid granulomatosis was first described as a distinct clinicopathological entity in 1972.[2] The diagnosis is based on the histological triad comprising the following:

Is lymphomatoid granulomatosis a lymphoproliferative disease?

Currently, lymphomatoid granulomatosis generally is considered a B-cell lymphoma associated with an exuberant, benign, T-cell reaction. In the initial description, it was not clear whether lymphomatoid granulomatosis represented a benign process that could progress to lymphoma or a malignant lymphoproliferative disease de novo. By 1990, the disease generally was viewed as an extranodal, angiocentric, T-cell lymphoma with a predilection for the lungs.

Scientific advances using flow cytometry and polymerase chain reaction (PCR) have allowed definitive cell phenotyping and assessment for T-cell receptor and immunoglobulin clonality, the hallmark of hematological malignancy. Surprisingly, these techniques have revealed that in most cases the large atypical cells represent malignant B cells and the T-cell component represents a prominent, polyclonal, reactive, T-cell infiltrate. It is best viewed as a T cell–rich, B-cell lymphoma.

Is lymphomatoid granulomatosis a response to opportunistic infection?

Speculation that lymphomatoid granulomatosis is due to an opportunistic pathogen is fueled by its frequent, though not exclusive, occurrence in patients with various forms of immune dysfunction. It is associated with Sjögren syndrome, chronic viral hepatitis, rheumatoid arthritis, renal transplantation, and human immune deficiency virus (HIV). In addition, a number of patients without associated immune system disorders have T-cell abnormalities.

Recent studies using a combination of PCR and in situ hybridization show that most lymphomatoid granulomatosis cases have malignant B cells containing Epstein-Barr virus (EBV) RNA. The biology of EBV infection involves binding to the complement receptor CD21 on B cells, resulting in the continuous growth or immortalization of infected B cells in vitro. In vivo, polyclonal, B-cell proliferation occurs, but it usually is controlled by immune regulation involving cytotoxic T cells. In immunodeficient states, the host's defenses may be unable to curb EBV-induced B-cell proliferation. In this regard, lymphomatoid granulomatosis shares characteristics with EBV-associated posttransplant lymphoma.

Epidemiology

Frequency

United States

Lymphomatoid granulomatosis is a rare disease of unknown prevalence.

Mortality/Morbidity

Lymphomatoid granulomatosis usually is progressive and fatal. In the largest studies, mortality rates range from 63-90% at 5 years; however, the clinical course is variable, with reports of prolonged courses and spontaneous remissions.

Race

No known racial predilection exists for lymphomatoid granulomatosis.

Sex

The male-to-female ratio of lymphomatoid granulomatosis is 2:1.

Age

Lymphomatoid granulomatosis is most common after the fifth to sixth decade of life.

History

The clinical features of lymphomatoid granulomatosis reflect systemic multiorgan disease. Pulmonary involvement usually is present, while the skin (50%), nervous system (25%), kidneys, and liver are affected less commonly. The lymph nodes, spleen, and bone marrow usually are spared until late in the course of illness. Araki et al reported primary orbital involvement.[3]

Causes

Other than its association with opportunistic disease and EBV, the etiology of lymphomatoid granulomatosis is unknown.

Laboratory Studies

No characteristic laboratory abnormalities exist in lymphomatoid granulomatosis.

Imaging Studies

Obtain chest radiographs. Results are usually abnormal but nonspecific. The radiologic differential diagnosis for lymphomatoid granulomatosis includes pseudolymphoma, malignant lymphoma, lymphocytic interstitial pneumonia, metastasis, sarcoidosis, Wegener granulomatosis, and cryptogenic organizing pneumonia. Some lesions regress, while others progress. Chest radiograph lesions and abnormalities include the following:

See the image below.



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Chest radiograph showing a dense, large, right upper lobe masslike infiltrate and bilateral nodular disease.

Hilar and mediastinal lymphadenopathy are rare and should prompt consideration of an alternative diagnosis or raise concern of transformation into aggressive lymphoma. Airway disease can involve the following:

Radiographic differential diagnoses can include the following:

Perform a chest CT scan. The role of CT scan requires further study. CT scan better defines pulmonary lesions, but findings are nonspecific. CT scan is useful for monitoring disease progression and response to treatment.

See the images below.



View Image

Contrast-enhanced chest CT scan showing poorly defined nodular peribronchovascular infiltrates with air-bronchograms.



View Image

Contrast-enhanced chest CT scan showing poorly defined nodular peribronchovascular infiltrates with air-bronchograms.

Perform brain imaging. CT scan shows high-density lesions. MRI lesions are isointense or hyperintense on T1-weighted images and hyperintense on T2-weighted images. Enhancement may be punctate and linear, a finding that can be relatively specific for inflammation of deep cerebral vessels.

Procedures

Perform a tissue diagnosis.

Histologic Findings

A definitive diagnosis of lymphomatoid granulomatosis requires the presence of the following histological triad:

A nodular perivascular infiltrate containing plasma cells, lymphocytes, and large atypical mononuclear cells in various stages of maturity is present. This is a destructive lesion due to vessel occlusion by lymphocytic infiltration and subsequent tissue necrosis.

Perform analysis for cell phenotype, clonality, and EBV infection. As discussed above, despite the predominance of T cells, the malignant cells appear to be B cells, and the T-cell infiltrate is polyclonal (see Pathophysiology). In general, the B-cell population is clonally expanded; however, oligoclonal populations have been identified in rare cases. A similar finding is described in posttransplant lymphoma and probably reflects an EBV-related phenomenon.

When peripheral nerve involvement exists, the infiltrate surrounds the nerve and causes spotty demyelination.

Medical Care

The therapeutic approach and optimal management have not been well defined. In several studies, therapy has ranged from observation to treatment with prednisone or chemotherapy. In the largest reported study of 152 patients, no significant difference in mortality or disease-free survival was found in treatment options, and the mortality rate exceeded 50%. New therapeutic approaches are necessary. In view of the association of lymphomatoid granulomatosis (LYG) with EBV and the similarity to posttransplant lymphoma, the use of antiviral drugs with minimal immunosuppressive therapy is advocated.

Medication Summary

No well-studied effective treatment exists for this disease. Apart from immunosuppressive regimens, experimental therapeutic options include interferon alfa-2b and ganciclovir.

Complications

Transformation into high-grade lymphoma may occur (13-47%).

Progressive respiratory disease with increasing respiratory failure may result in pneumothorax, infection, and hemorrhage.

Hemoptysis, occasionally massive, may complicate cavitation of the diseased pulmonary tissue.

Pneumothorax may occur.

Opportunistic infections may develop.

Seizures, mental status changes, mononeuropathy, or diabetes insipidus may complicate progressive neurological disease.

Prognosis

The median survival from diagnosis is 14 months. More than 60% of patients die within 5 years.

The cause of death is usually extensive destruction of the pulmonary parenchyma, resulting in respiratory failure, sepsis, and, occasionally, massive hemoptysis.

Poor prognostic indicators include an age younger than 30 years, neurological or hepatic involvement, leukopenia or pancytopenia, and anergy.

Author

Nader Kamangar, MD, FACP, FCCP, FCCM, Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Chief, Division of Pulmonary and Critical Care Medicine, Vice-Chair, Department of Medicine, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Anthony W O'Regan, MD, Clinical Lecturer of Medicine, Department of Internal Medicine, Section of Respiratory Medicine, National University of Ireland, Galway; Adjunct Professor of Medicine, Boston University Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Ryland P Byrd, Jr, MD, Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Disclosure: Nothing to disclose.

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Chest radiograph showing a dense, large, right upper lobe masslike infiltrate and bilateral nodular disease.

Contrast-enhanced chest CT scan showing poorly defined nodular peribronchovascular infiltrates with air-bronchograms.

Contrast-enhanced chest CT scan showing poorly defined nodular peribronchovascular infiltrates with air-bronchograms.

Chest radiograph showing a dense, large, right upper lobe masslike infiltrate and bilateral nodular disease.

Contrast-enhanced chest CT scan showing poorly defined nodular peribronchovascular infiltrates with air-bronchograms.

Contrast-enhanced chest CT scan showing poorly defined nodular peribronchovascular infiltrates with air-bronchograms.