Lymphomatoid Granulomatosis

Updated: Dec 31, 2015
  • Author: Nader Kamangar, MD, FACP, FCCP, FCCM; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

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.

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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:

  • 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.

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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.

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