Lymphomatoid Granulomatosis

Background

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus–associated systemic angiodestructive lymphoproliferative disease histopathologically defined by angiocentric, angioinvasive and extranodal lesions with polymorphic lymphocyte infiltration.^{[1, 2]} In the 2016 WHO classification of mature lymphoid, histiocytic, and dendritic neoplasms, it is categorized as a mature B-cell neoplasm.^[3]

Lymphomatoid granulomatosis typically presents in the fourth and fifth decades of life and is considered a systemic disease; lung involvement is the most frequent, but skin,^{[4, 5, 6]} central nervous system (CNS), kidney, and liver can also be involved.^{[2, 7]} A small number of patients with isolated lymphomatoid granulomatosis of the CNS (CNS-LYG) have been reported.^[8] Although nodal and/or bone marrow involvement can occur,^[9] this is extremely rare and should prompt evaluation for an alternative diagnosis.^[2]

The therapy used varies but usually depends on histologic grading, symptoms severity, extension of extrapulmonary involvement, and underlying immunosuppression.^{[10, 11]}

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Pathophysiology

The pathogenesis of lymphomatoid granulomatosis is unknown; however, there is overwhelming evidence that lymphomatoid granulomatosis is a distinctive type of malignant lymphoma associated with immunosuppression.^[12] Lymphomatoid granulomatosis also occurs in patients with immunosuppressive conditions (acquired immunodeficiency syndrome [AIDS],^{[13, 14]} Wiskott-Aldrich syndrome, and post transplantation) and autoimmune conditions (Sjogren syndrome, rheumatoid arthritis, systemic lupus erythematosus, and Crohn disease).^[15] Simultaneous presentation of multiple myeloma and lymphomatoid granulomatosis in rheumatoid arthritis patients is also reported.^[16]

Lymphomatoid granulomatosis was first described as a distinct clinicopathologic entity in 1972.^[1] The diagnosis is based on the histologic 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)

Lymphomatoid granulomatosis is considered a distinct form of T cell-rich large B-cell lymphoma. The presence of Epstein-Barr virus (EBV) in the large B cells in lymphomatoid granulomatosis has been confirmed in numerous studies, and large B cells showing the presence of EBV-positive cells by in situ hybridization with the EBER probe is now definitional for lymphomatoid granulomatosis according to the WHO.^[3]

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Epidemiology

Lymphomatoid granulomatosis is a rare disease of unknown prevalence. Males are affected twice as often as females, and the condition is most common in adults aged 40s-60s. No known racial predilection exists.

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Prognosis

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. The median survival from diagnosis is 14 months. 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, neurologic or hepatic involvement, leukopenia or pancytopenia, and anergy. 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 and opportunistic infections may develop. Seizures, mental status changes, mononeuropathy, or diabetes insipidus may complicate progressive neurologic disease.

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History

The clinical features of lymphomatoid granulomatosis reflect systemic multiorgan disease. Pulmonary involvement is common (>90%), whereas the skin (25-50%), nervous system (25-50%), kidneys (40-50%), and liver, spleen, and lymph nodes (10%) are affected less commonly.^[10] The lymph nodes, spleen, and bone marrow are usually spared until late in the course of illness. Two cases of primary orbital involvement and a case of hard palate involvement have been reported.^{[17, 18, 19]}

Pulmonary involvement includes the following features:

• 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 involvement includes the following features:

• Patchy, occasionally painful, erythematous macules, papules, and plaques typically involve the gluteal regions and extremities.^[20]
• Erythema may involve nodosumlike subcutaneous nodules that may ulcerate but are often truncal.
• Isolated cutaneous lymphomatoid granulomatosis has been reported.

Nervous system involvement includes the following features:

• Extensive lymphocytic infiltration of the meninges, cerebral vessels, and peripheral nerves is found in as many as 25% of patients.
• Central nervous system involvement may include mass lesions; neurologic manifestations, including mental status changes, ataxia, hemiparesis, and seizures, may occur.
• Peripheral nerve involvement is uncommon^[10] ; it may include distal sensory neuropathy or mononeuritis multiplex.
• Isolated neurologic lymphomatoid granulomatosis has been reported.^{[21, 22]}

Renal involvement includes the following features:

• Clinically significant renal disease is uncommon.
• At autopsy, renal involvement is present in 45% of cases.
• Unlike granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), glomerulonephritis is not a feature of lymphomatoid granulomatosis.

Liver involvement includes the following features:

• Frequently found at autopsy (29% of cases), but clinical disease is rare.
• Hepatomegaly is present in 12% of cases and may carry a worse prognosis.

Ophthalmic manifestations are rare. Conjunctival, pupillary, choroidal, retinal, optic nerve, and orbital (including lacrimal gland) involvement have been reported.^[18]

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Laboratory Studies

No characteristic laboratory abnormalities exist in lymphomatoid granulomatosis. Note the following:

• White blood cell (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.
• Renal and liver function study findings are usually normal.
• Urinalysis results are usually normal.
• Cerebrospinal fluid (CSF) analysis may show elevated protein levels with pleocytosis.^[11]
• Delayed-type hypersensitivity and lack of anergy have been reported in more than 50% of cases.

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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, granulomatosis with polyangiitis, 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.

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Lymphomatoid Granulomatosis. 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 granulomatosis with polyangiitis and sarcoidosis
• Eosinophilic granulomatosis
• Amyloidosis

Perform chest computed tomography (CT) scanning, albeit the role of CT scanning requires further study. This imaging modality better defines pulmonary lesions, but findings are nonspecific. CT scanning is also useful for monitoring disease progression and response to treatment.

CT findings can include the following^[23] :

• Nodules, masses
• Consolidation in perilymphatic distribution
• Cavitary lesions
• Mediastinal lymphadenopathy (uncommon)

See the images below.

View Image

Lymphomatoid Granulomatosis. Contrast-enhanced chest computed tomography scan showing poorly defined nodular peribronchovascular infiltrates with air-....

View Image

Lymphomatoid Granulomatosis. Contrast-enhanced chest computed tomography scan showing poorly defined nodular peribronchovascular infiltrates with air-....

F18-FDG PET/CT scans show increased FDG uptake of the lesions.^{[24, 25, 26]} This imaging modality can be used to monitor disease progression and treatment response, such as in high-grade pulmonary lymphomatoid granulomatosis, as well as to demonstrate multisystem disease distribution and guide high-yield biopsy.^[27]

For patients with central nervous system involvement, CT scanning shows high-density lesions. On magnetic resonance imaging (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.

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Procedures

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. Inform the pathologist that lymphomatoid granulomatosis is clinically suspected to ensure that appropriate studies are performed.

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Histologic Findings

A definitive diagnosis of lymphomatoid granulomatosis requires the presence of the following histologic 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 Epstein-Barr virus (EBV) infection. Despite the predominance of T cells, the malignant cells appear to be B cells, and the T-cell infiltrate is polyclonal. 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.

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Staging

Lymphomatoid granulomatosis is pathologically divided into three grades related to the proportion of Epstein-Barr virus (EBV) positive B cells relative to the reactive background lymphocytes, as follows^[28] :

• Grade 1: Infrequent EBV positive cells (< 5/HPF)
• Grade 2: EBV positive large lymphoid cells or immunoblasts (5-50/HPF)
• Grade 3: Large atypical CD20+ B cells with extensive necrosis and >50/HPF EBV positive cells

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Approach Considerations

Patients with a benign course of lymphomatoid granulomatosis (LYG) require no treatment. Spontaneous remission has been reported^[10] ; however, symptomatic or progressive disease should be treated. More than 50% of patients with lymphomatoid granulomatosis respond to treatment; however, the best therapeutic approach and optimal management have not been well defined.

No definitive treatment exists yet. Treatment for lymphomatoid granulomatosis is generally directed at boosting the immune response to Epstein-Barr virus (EBV). Low-grade lymphomatoid granulomatosis is hypothesized to be mediated by an immune–dependent process, whereas high-grade lymphomatoid granulomatosis is thought to be mediated by an immune–independent process.^[2] High-grade lymphomatoid granulomatosis is less likely to respond to immune response augmentation strategies and requires a combination of immune modulation and/or combination immunochemotherapy.^[2] Recurrence is usual and may include refractory disease or progression to high-grade lymphoma (13-47%).^{[2, 29]}

A case report of four patients with biopsy-proven primary LYG of the central nervous system (CNS) has described using therapy similar to that of aggressive CNS lymphomas—that is, high-dose chemotherapy (HCT) (eg, methotrexate, thiotepa, cytarabine, carmustine, rituximab) with autologous stem cell transplantation (ASCT).^[30] All four patients showed no evidence of systemic involvement. At a post HCT-ASCT follow-up time of 28 and 36 months, respectively, two of the four patients remained alive and free of disease. One of the remaining patients had severe immunodeficiency and died 50 days post HCT-ASCT from refractory pneumonia. The final remaining patient had had LYG disease progression while undergoing HCT-ASCT and died 5 days following transplantation from deterioration of fulminant disease.^[30]

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Medical Care

Treatment recommendations for lymphomatoid granulomatosis (LYG) are based on the grade of disease. In patients with low-grade disease (grade I/II), interferon alfa-2b has been shown to be highly effective in most patients, leading to long-term remissions.^[31] Relapse after treatment with interferon alfa-2b can be retreated with interferon alfa-2b in disease that remains low grade. High-grade disease is treated with combination chemotherapy with rituximab.^{[32, 33]} Cross-over therapy can be considered for patients with high-grade disease who develop low-grade disease following combination immunochemotherapy or patients with low-grade disease who have disease progression to high-grade disease following interferon alfa treatment.^[2]

Corticosteroids alone should not be used for long-term control of lymphomatoid granulomatosis. Similarly, rituximab alone is seldom effective for long-term control.^[34] Neither of these agents effectively eradicates abnormal Epstein-Barr virus (EBV) clones, and corticosteroids can increase immusuppression and, ultimately, disease progression.

Further study is needed to evaluate the efficacy of PD-1 inhibitor, nivolumab, for treating lymphomatoid granulomatosis as well as hematopoietic stem cell transplantation for primary refractory and multiple relapsed lymphomatoid granulomatosis.^[2]

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

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Medication Summary

The most effective therapy for individuals with lymphomatoid granulomatosis is unknown. In addition to immunosuppressive regimens, experimental therapeutic options include interferon alfa-2b and rituximab.

Interferon alfa-2b has antiviral, antiproliferative, and immunomodulatory effects. The association with EBV and posttransplant lymphoma prompted a group to treat lymphomatoid granulomatosis with interferon alfa-2b. 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.^[31]

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.^{[32, 33, 35, 36, 37, 38]} These case reports have involved patients with advanced disease refractory to other medical therapies.^{[39, 40]} Although some of these case reports appear promising, larger studies are needed to substantiate the efficacy of rituximab in the treatment of lymphomatoid granulomatosis.

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