Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder

Abstract

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV, with most patients showing evidence of immune dysfunction, despite no known primary immunodeficiency. Pathologically, LYG is graded by the number and density of EBV+ atypical B cells, and other characteristic findings include an angioinvasive/angiodestructive reactive T-cell infiltrate and various degrees of necrosis. Clinically, LYG universally involves the lungs with other common extranodal sites, including skin, central nervous system, liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and, if present, suggests an alternative diagnosis. Treatment selection is based on histologic grade and underlying pathobiology with low-grade disease hypothesized to be immune-dependent and typically polyclonal and high-grade disease to be immune-independent and typically oligoclonal or monoclonal. Methods of augmenting the immune response to EBV in low-grade LYG include treatment with interferon-α2b, whereas high-grade disease requires immunochemotherapy. Given the underlying defective immune surveillance of EBV, patients with high-grade disease may have a recurrence in the form of low-grade disease after immunochemotherapy, and those with low-grade disease may progress to high-grade disease after immune modulation, which can be effectively managed with crossover treatment. In patients with primary refractory disease or in those with multiple relapses, hematopoietic stem cell transplantation may be considered, but its efficacy is not well established. This review discusses the pathogenesis of LYG and highlights distinct histopathologic and clinical features that distinguish this disorder from other EBV+ B-cell LPDs and lymphomas. Treatment options, including immune modulation and combination immunochemotherapy, are discussed.

Graphical abstract

Figure 1.

Pathologic findings and histologic grading of LYG. Histologic grading of LYG is based on the number and density of EBV⁺ atypical B cells and degree of coagulative necrosis. Low-grade (grades 1 and 2) disease is characterized by sparse EBER⁺ atypical B cells, as well as focal or absent coagulative necrosis. An increased number and size of EBER⁺ atypical B cells are seen in high-grade (grade 3) disease with often-extensive coagulative necrosis. A reactive angiocentric and angiodestructive CD3⁺ T-cell infiltrate is another characteristic pathologic feature across all grades of the disease. An increased frequency of monoclonality by molecular analysis is seen with higher grades of disease, likely representative of the progressive transformation of EBV-infected B cells.

Figure 2.

Systemic imaging and cutaneous manifestations of LYG. Computed tomography (CT) of the chest in a 25-year-old man (A) showed multiple, bilateral nodular masses affecting the mid to lower lung fields and in a 43-year-old man (B) showed central necrosis and cavitation in some of the nodular pulmonary lesions. CT of the abdomen in a 57-year-old woman (C) showed multiple, bilateral renal masses and in a 52-year-old man (D) revealed 2 hypodense liver lesions. Photographs of the skin of a 56-year-old man (E), with an erythematous dermal papule without ulceration, and of a 29-year-old man (F), with a white plaquelike lesion with surrounding erythema.

Figure 3.

CNS imaging findings in LYG. T1-weighted postcontrast (A,D), T2-weighted (B,E), and fluid attenuation inversion recovery (C,F) sequences from MRI of the brain in a 43-year-old woman (A-C) with LYG demonstrates a large, enhancing right temporal lesion with central necrosis, and in a 39-year-old man (D-F) with LYG demonstrates a large, enhancing left posterior occipital lesion with central necrosis.