Lymphomatoid Granulomatosis

Updated: Jan 03, 2023
  • Author: Nazir A Lone, MD, MBBS, MPH, FACP, FCCP; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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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]



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]



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.



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.