NORD gratefully acknowledges Elaine S. Jaffe, MD, Chief, Hematopathology Section, Lab of Pathology, National Cancer Institute, and Wyndham H. Wilson, M.D, Ph.D, Senior Investigator, Metabolism 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, kidneys or central nervous system 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 overproduction 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 (less than 5 percent).
In almost all affected individuals, lymphomatoid granulomatosis affects the lungs and often causes a cough, shortness of breath (dyspnea) and 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. Affected individuals may occasionally develop numbness and tingling and/or weakness of their lower extremities.
Approximately 40-50 percent 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 30 percent 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 Sjogren syndrome, rheumatoid arthritis or chronic viral hepatitis.
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 T-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 adults after the fifth decade, 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 affect 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 patients with grade I/II disease, interferon alfa-2b has been shown to be highly effective in most patients, and leads to long-term remissions, Patients who relapse after treatment with interferon alfa-2b and still have low-grade disease can be re-treated with interferon alfa-2b. In patients with grade III disease, interferon alfa-2b is not effective, and combination chemothearpy with rituximab should be used. However, there is a frequent rate of recurrence with grade I/II disease following chemotherpy-rituximab in grade III disease.
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 control. Neither of these agents effectively eradicates and abnormal EBV clones and corticosteroids can increase immusuppression and ultimately disease progression.
If patients develop lymphomatoid granulomatosis on immune suppressive agents, they should be discontinued if at all possible since this may induce clinical remission. If the disease is progressive or advanced, then treatment as outlined above should be instituted.
Patients with 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 chemothearpy. Rarely patients with CNS involvement require brain radiation.
Researchers at the Division of Clinical Sciences of the National Cancer Institute seek additional patients for a study of treatment of Lymphomatoid Granulomatosis with interferon alfa-2b for grade I/II and EPOCH-Rituximab /Alpha-Interferon for Grade III. To participate, patients must be diagnosed with LYG, 12 or older, and not pregnant or nursing.
For information, contact Dr. Wyndham H. Wilson, the principal investigator, at (301) 435-2415, [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]
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Jaffe ES, Wilson W. Lymphomatoid Granulomatosis. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:48-49.
Patsalides AD, Atac G, Hedge U, et al. Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging. Radiology. 2005;237:265-273.
McCloskey M, Catherwood M, McManus G, et al. A case of lymphomatoid granulomatosis masquerading as a lung abscess. Thorax. 2004;59:818-819.
Brown JR, Skarin AT. Clinical mimics of lymphoma. Oncologist. 2004;9:406-416.
Guven A, Baskin D. Lymphomatoid granulomatosis in a boy with long-term follow-up. Ped Hem Onc. 2001;18:377-382.
Moertel CL, Carlson-Green B, Watterson BA, Simonton SC. Lymphomatoid granulomatosis after childhood acute lymphoblastic leukemia: report of effective therapy. Pediatrics. 2001;107:e82.
Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biological features. Am J Surg Pathol. 2001;25:1111-1120.
Petrella TM, Walker IR, Jones GW, Leber B. Radiotherapy to control CNS lymphomatoid granulomatosis: a case report and review of the literature. Am J Hematol. 1999;62:239-241.
Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Cancer Surv. 1997;30:233-48.
Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood. 1996;87:4531-4537.
Kamangar N. Lymphomatoid Granulomatosis. Medscape http://emedicine.medscape.com/article/299751-overview Updated December 31, 2015. Accessed April 21, 2016.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100