NORD gratefully acknowledges Elaine S. Jaffe, MD, Chief, Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Christopher Melani, MD, Assistant Research Physician, Lymphoid Malignancies Branch, National Cancer Institute and Wyndham H. Wilson, MD, PhD, Senior Investigator, Lymphoid Malignancies Branch, National Cancer Institute, for assistance in the preparation of this report.
Lymphomatoid granulomatosis is a rare disorder characterized by overproduction (proliferation) of white blood cells called lymphocytes (lymphoproliferative disorder). The abnormal cells infiltrate and accumulate (form lesions or nodules) within tissues. The lesions or nodules damage or destroy the blood vessels within these tissues. The lungs are most commonly affected in lymphomatoid granulomatosis. Symptoms often include cough, shortness of breath (dyspnea) and chest tightness. Other areas of the body such as the skin, central nervous system, kidneys and liver are also frequently affected.
The abnormal cells in lymphomatoid granulomatosis are B-cells (B lymphocytes) containing the Epstein-Barr virus. There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes. Because lymphomatoid granulomatosis is caused by the growth of abnormal B-cells, affected individuals may eventually develop B-cell lymphoma, a form of non-Hodgkin lymphoma. Lymphoma is a general term for cancer of the lymphatic system.
The symptoms and progression of lymphomatoid granulomatosis vary greatly from person to person. The disorder may occasionally resolve without treatment (spontaneous remission) in some affected individuals or more commonly it will progress and cause life-threatening complications. Occasionally, it is an incidental and asymptomatic finding on chest radiographs.
In almost all affected individuals, lymphomatoid granulomatosis affects the lungs and often causes a cough, shortness of breath (dyspnea) and/or chest tightness. In most patients, the cough is non-productive and is rarely associated with blood (hemoptysis). Systemic symptoms are not uncommon and may include fever, a general feeling of poor health (malaise), weight loss, and fatigue.
Approximately one-third of affect individuals will develop skin lesions such as a patchy reddish (erythematous) rash consisting of flat discolored lesions (macules), small, elevated bumps (papules) or, more rarely, solid, raised, flat-topped lesions (plaques). Small bumps or growths (nodules) just below the surface of the skin (subcutaneous) may also develop. Larger nodules may become open sores (ulcerated).
In approximately one-third of patients, the central nervous may be involved potentially resulting in mental status changes, headaches, seizures, paralysis of one side of the body (hemiparesis), or loss of the ability to coordinate voluntary movements (ataxia).
Less commonly, the kidneys or liver may be involved, although this rarely leads to the development of symptoms. In some cases the liver may become enlarged (hepatomegaly). In some extremely rare cases, lymphomatoid granulomatosis may only affect the skin or only the central nervous system (isolated lymphomatoid granulomatosis).
Lymphomatoid granulomatosis may eventually progress to a form of large B-cell lymphoma.
The exact cause of lymphomatoid granulomatosis is unknown. Lymphomatoid granulomatosis occurs with greater frequency in individuals with some form of immune system dysfunction including individuals with human immunodeficiency virus (HIV) infection and Wiskott-Aldrich syndrome. In most patients the cause of the immune dysfunction is unknown.
It is likely that some combination of immunodeficiency, genetic and familial factors all play a role in the development of lymphomatoid granulomatosis. The therapy used varies, but is generally directed against eliminating the EBV-infected B-cells or boosting the immune system.
The classification of lymphomatoid granulomatosis has been difficult. Originally, the disorder was viewed as a benign process with the potential to progress to malignant lymphoma. Researchers believed that defective cells were T-cells. Scientific advances in technology have allowed researchers to determine that the abnormal cells in lymphomatoid granulomatosis are B-cells infected by the Epstein-Barr virus. However, most of the cells within the tissues are T-cells, reacting against the abnormal EBV-infected B-cells. The Epstein-Barr virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects.
Lymphomatoid granulomatosis affects males twice as often as females. It is most common in middle-age adults in the fourth to sixth decade of life, but can occur at any age and has been reported in children. The prevalence of lymphomatoid granulomatosis is unknown.
The disorder was first described in the medical literature in 1972.
A diagnosis of lymphomatoid granulomatosis is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests such as the surgical removal and microscopic examination (biopsy) of tissue samples taken from an affected organ such as the lungs. A skin biopsy is not reliable because the characteristic abnormal cells may be missing.
Certain x-ray studies (e.g., CT scans) may be able to aid in diagnosis. A CT scan of the lungs or another affected organ can help determine the extent of lymphomatoid granulomatosis. Magnetic resonance imaging (MRI) of the brain and lumbar puncture (LP) should be performed to rule out involvement of the central nervous system.
The most effective therapy for individuals with lymphomatoid granulomatosis is unknown. For individuals with minimal disease, observation may be recommended since long-term survival without treatment has occurred as well as spontaneous remission. In most cases, however, treatment is recommended. Treatment recommendations are based on the grade of disease. Lymphomatoid granulomatosis is pathologically divided into three grades (I, II, III), which are determined by the number of EBV+ B-cells and the extent of necrosis. In most patients with low-grade (grade I/II) disease, immune-modulation with interferon alfa-2b has been shown to be highly effective and leads to long-term remission in a subset of patients. Patients who relapse after treatment with interferon alfa-2b and still have low-grade disease can be retreated with interferon alfa-2b. In patients with high-grade (grade III) disease, interferon alfa-2b is not effective, and combination chemotherapy with rituximab should be used. However, there is a frequent rate of recurrence with low-grade disease following chemotherapy+rituximab in high-grade disease and this frequently responds to treatment with interferon alfa-2b.
Corticosteroids alone are only recommended as a temporizing measure and should not be used for long term control of lymphomatoid granulomatosis. Similarly, rituximab alone is seldom effective for long term disease control. Neither of these agents effectively eradicates the abnormal EBV clones and corticosteroids can further increase immunosuppression and ultimately accelerate disease progression.
If patients develop lymphomatoid granulomatosis on immunosuppressive agents, they should have these agents discontinued if at all possible since this may lead to clinical remission. If the disease is progressive or advanced, then treatment as outlined above should be instituted.
Patients with low-grade (grade I/II) disease in the central nervous system (CNS) frequently respond to interferon alpha-2b and do not require intrathecal or high dose systemic chemotherapy. Rarely patients with CNS involvement require brain radiation.
Additionally, newer methods of augmenting the immune-system using agents termed immune-checkpoint inhibitors are being testing in patients with both low-grade and high-grade lymphomatoid granulomatosis as well as other EBV+ lymphoproliferative diseases and lymphomas.
Researchers at the National Cancer Institute seek additional patients for a study on the natural history and treatment of lymphomatoid granulomatosis with interferon alfa-2b for low-grade (grade I/II) and dose-adjusted EPOCH-Rituximab /Alpha-Interferon for high-grade (grade III) disease as well as a study of nivolumab in EBV+ lymphoproliferative disorders, including lymphomatoid granulomatosis, and EBV+ non-Hodgkin’s lymphomas. To participate, patients must be diagnosed with LYG, 12 years of age or older, and not pregnant or nursing.
For information, contact Dr. Wyndham H. Wilson, the principal investigator, at (301) 312-5484, [email protected] or visit:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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