eMedicine Specialties > Pulmonology > Idiopathic Lung Disorders

Lymphomatoid Granulomatosis

Author: Nader Kamangar, MD, FACP, FCCP, FAASM,, Associate Professor of Clinical Medicine, Director of Hospitalist/Intensivist Program, Division of Pulmonary, Critical Care and Sleep Medicine, David Geffen School of Medicine at University of California Los Angeles; Associate Director, Combined Pulmonary and Critical Care Fellowship Program, Cedars-Sinai/Olive View-UCLA/West Los Angeles Veterans Affairs Medical Center
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
Contributor Information and Disclosures

Updated: Apr 16, 2009

Introduction

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.

Lymphomatoid granulomatosis was first described as a distinct clinicopathological entity in 1972.¹ The diagnosis is based on the histological triad comprising the following:

• Nodular polymorphic lymphoid infiltrate composed of small lymphocytes, plasma cells, and variable numbers of large atypical mononuclear cells
• Angiitis due to transmural infiltration of arteries and veins by lymphocytes (a process distinct from vasculitis in which acute and chronic inflammatory cells are found with associated vessel wall necrosis)
• Granulomatosis (central necrosis within the lymphoid nodules and not granuloma formation)

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.

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.

Clinical

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.²

• Pulmonary involvement
  • Cough and dyspnea are present in most patients.
  • Sputum production may reflect associated pneumonia.
  • Hemoptysis usually indicates disease cavitation.
• Systemic presentation of lymphoma-related B symptoms: Patients may have fever, weight loss, and malaise.
• Skin
  • Patchy, occasionally painful, erythematous macules, papules, and plaques typically involve the gluteal regions and extremities.³
  • Erythema may involve nodosumlike subcutaneous nodules that may ulcerate but are often truncal.
  • Isolated cutaneous lymphomatoid granulomatosis has been reported.
• Nervous system
  • Extensive lymphocytic infiltration of the meninges, cerebral vessels, and peripheral nerves is found in as many as 25% of patients.
  • CNS may include mass lesions. Neurological manifestations, including mental status changes, ataxia, hemiparesis, and seizures, may occur.
  • Peripheral nerve involvement may include distal sensory neuropathy or mononeuritis multiplex.
  • Isolated neurological lymphomatoid granulomatosis has been reported.^4,5
• Renal
  • Clinically significant renal disease is uncommon.
  • At autopsy, renal involvement is present in 45% of cases.
  • Unlike WG, glomerulonephritis is not a feature of lymphomatoid granulomatosis.
• Liver
  • Hepatic involvement also is frequent at autopsy (29% of cases), but clinical disease is rare.
  • Hepatomegaly is present in 12% of cases and may carry a worse prognosis.

Causes

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

• Search for CME/CE on This Topic »

• Wegener Granulomatosis (Neurology)

• Waxing and Waning Pulmonary Nodules and Myelodysplastic Syndrome
• Multiple Cranial Neuropathies