Lymphomatoid Granulomatosis 

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

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.

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.

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.

 

Presentation

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]

  • 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.[4]

    • 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.[5, 6]

  • 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.

 

DDx

Diagnostic Considerations

The differential diagnosis of the clinical and radiological manifestations of lymphomatoid granulomatosis (LYG) is extensive and beyond the scope of this article. When tissue is available for histology, the following 2 groups of diseases need to be differentiated from lymphomatoid granulomatosis:

  • Other types of pulmonary granulomatosis

    • Bronchocentric granulomatosis and Churg-Strauss (allergic angiitis and granulomatosis) are characterized by asthma and eosinophilia, which are not features of lymphomatoid granulomatosis.

    • Necrotizing sarcoid granulomatosis has nodular pulmonary sarcoid lesions that mimic lymphomatoid granulomatosis. Unlike lymphomatoid granulomatosis, in necrotizing sarcoid, mediastinal adenopathy often occurs; extrapulmonary disease rarely exists; and histology demonstrating well-formed granulomas with central necrosis also exists.

    • WG, unlike angiitis seen in lymphomatoid granulomatosis, is a true vasculitis with acute and chronic inflammatory cells and vessel destruction. Sinus, upper airway, and renal involvement with necrotizing glomerulonephritis are common in WG but rare in lymphomatoid granulomatosis.

  • Other types of malignant lymphoma

    • Hodgkin disease is different because pulmonary involvement without mediastinal adenopathy is rare. The diagnosis requires demonstration of Reed-Sternberg cells.

    • Nasal angiocentric lymphoma (NAL), also known as polymorphic reticulosis or lethal midline granuloma, and lymphomatoid granulomatosis initially were believed to be the same disease, with the former predominantly affecting the upper airway. Recent work has shown that NAL is an EBV-related, natural killer (NK) cell lymphoma and a separate disease entity. Lymphomatoid granulomatosis does not affect the upper airway and nasal passages.

    • Non-Hodgkin lymphoma has well-described pulmonary and extranodal involvement. In particular, peripheral T-cell lymphomas are characterized by vascular infiltration and a degree of morphological heterogeneity. Careful histological diagnosis and studies to determine clonal expansion of T cells are required to rule out lymphomatoid granulomatosis.

Differential Diagnoses

 

Workup

Laboratory Studies

No characteristic laboratory abnormalities exist in lymphomatoid granulomatosis.

  • Obtain a WBC count.

    • Leukopenia (20%) and lymphopenia (33%) may be present.

    • CD4 lymphocyte count may be low.

    • Leukocytosis greater than 10,000 cells/μ L is rare.

  • Hematocrit is normal or slightly elevated.

  • Erythrocyte sedimentation rate (ESR) has mild-to-moderate elevation but may be normal.

  • Obtain renal and liver function studies. Findings are usually normal.

  • Urinalysis results are usually normal.

  • Delayed-type hypersensitivity and lack of anergy have been reported in more than 50% of cases.

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:

  • Bilateral nodules or masses in the lower and peripheral lung fields (80-100%). These nodules may occasionally be migratory in nature.

  • Pleural effusions (33%)

  • Pneumonitis or large masslike lesion (30%)

  • Cavitation of nodules (30%)

  • Pneumothorax (5%)

See the image below.

Chest radiograph showing a dense, large, right upp 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:

  • Distal small airway

  • Main bronchial disease (occasionally)

  • Atelectasis or lobar collapse on chest films

Radiographic differential diagnoses can include the following:

  • Primary pulmonary and metastatic malignancy

  • Granulomatous diseases, including WG and sarcoidosis

  • Eosinophilic granulomatosis

  • Amyloidosis

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.

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

  • In general, perform a biopsy on the most accessible organ involved.

  • Establishing the diagnosis of lymphomatoid granulomatosis usually requires an open lung or video-assisted thoracoscopic biopsy. Transbronchial lung biopsy has not been studied rigorously. Because of the focal nature of lymphomatoid granulomatosis and the fact that it is not bronchocentric, a low diagnostic yield with bronchoscopic transbronchial biopsies is likely. In one study, the diagnosis was established with the aid of open lung biopsy in 70% of cases, bronchoscopic lung biopsy in 15% of cases, and extrapulmonary biopsy in 15% of cases. In cases where bronchoscopic lung biopsy is nondiagnostic, a thoracoscopic lung biopsy may be necessary.

  • Skin biopsy is the least invasive.

  • In all cases, inform the pathologist that lymphomatoid granulomatosis is clinically suspected to ensure that appropriate studies are performed.

Histologic Findings

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

  • Polymorphic lymphocytic infiltrate

  • Angiitis

  • Granulomatosis (central necrosis)

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.

 

Treatment

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.

  • Patients with a benign course require no treatment. Spontaneous remission has been reported.

  • Corticosteroids, with or without chemotherapy, may be recommended.

    • Treat symptomatic or progressive disease.

    • In general, therapy involves prednisone with antineoplastic agents (eg, cyclophosphamide).

    • More than 50% of patients with lymphomatoid granulomatosis respond to treatment.

    • Recurrence is usual and may include refractory disease or progression to high-grade lymphoma (13-47%).

    • When lymphomatoid granulomatosis progresses to high-grade lymphoma, combination antilymphoma regimens are used, but response rates are poor at this stage.

  • Localized disease may respond to radiotherapy.

  • Surgical resection of isolated pulmonary masses followed by chemotherapy has been associated with disease-free survival for at least 2 years.

  • Other treatment options include ganciclovir, interferon alfa-2, or, depending on histologic grade, combination chemotherapy.[7, 8]

 

Medication

Medication Summary

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

  • Interferon alfa-2b

    • The association with EBV and posttransplant lymphoma prompted a group to treat lymphomatoid granulomatosis with interferon alfa-2b.[9]

    • This drug has antiviral, antiproliferative, and immunomodulatory effects.

    • All 4 patients who were treated responded, with 3 patients achieving a complete response at 3 months.

    • Most patients responded to a dosage of 10 million units administered subcutaneously 3 times a week.

    • At follow-up of 36-60 months, 3 patients remained disease-free.

  • Ganciclovir

    • A patient with lymphomatoid granulomatosis and positive EBV serology post–stem cell transplant for multiple myeloma was reported to have complete radiologic remission following 2 weeks of ganciclovir therapy.

    • It should be noted that immune reconstitution also coincided with recovery.

  • Rituximab[10, 11, 12, 13]

    • Rituximab is a monoclonal antibody that targets the B-cell surface molecule CD20. Several case reports of the efficacy of monoclonal antibodies have been published.[14, 15, 16] These case reports have involved patients with advanced disease refractory to other medical therapies.[17, 18]

    • Although some of these case reports appear promising, larger studies are needed to substantiate the efficacy of rituximab in the treatment of lymphomatoid granulomatosis.

 

Follow-up

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.