Angiocentric lymphoproliferative disorders of the respiratory system: incrimination of Epstein-Barr virus in pathogenesis.

ETHAL MIDLINE granuloma and lymphomatoid L granulomatosis are related angiocentric, angiodestructive lymphoproliferative disorders that involve the upper and lower respiratory tracts, respectively. They are both characterized by a heterogeneous infiltrate composed of small lymphocytes, mononuclear phagocytes, plasma cells, occasional eosinophils, and variable numbers of large, atypical lymphoid cells, not unlike the reactive infiltrate observed in Hodgkin’s disease. Because of the lack of a predominant, clearly malignant population identifiable on histopathologic examination, these two clinicopathologic entities were assigned to a pathologic purgatory of descriptive diagnostic designations instead of classification as a non-Hodgkin’s lymphoma, despite a malignant clinical course in the absence of therapy. A historical perspective shows that current technologies have provided profound molecular insights into the nature of this spectrum of lymphoproliferative disorders, although many questions remain. The report by Borisch et all in this issue of Blood demonstrates that a subtype of Epstein-Barr virus (EBV) commonly isolated from immunocompromised individuals is frequently associated with midline granuloma. Typically, reports of lethal midline granuloma describe a prodromal phase with nasal symptoms of months to years duration, followed by the onset of ulcers that efface midline nasopharyngeal structures, resulting in fatal complications related to cachexia, hemorrhage, or infection. Originally, Edgerton and DesPrez2 questioned the nature of lethal midline granuloma: “It is still an unsolved question whether lethal midline granuloma represents a tumour unlike all other tumours, an infection unlike other infections, or a defect in the immune mechanism.” Similarly, Liebow et a13 speculated that there would be controversy as to whether or not lymphomatoid granulomatosis should be classified as a malignant lymphoma. Subsequently, a critical review of nasal lymphoproliferative lesions seen at the Mayo Clinic4 resolved a group constituting approximately 27% of cases, which were composed of a heterogeneous infiltrate that included varying numbers of atypical lymphoid cells associated with necrosis and invasion of blood vessels, as well as chronic changes such as fibrosis, epithelial metaplasia, and hyperplasia, and glandular atrophy, perhaps sequelae of a chronic infection. This group, designated polymorphic reticulosis, had a favorable prognosis and a mean symptomatic interval that was tenfold longer (55 months v 5 months) than was observed in patients with histopathologically proved lymphomas. These lesions were presumed to represent the histologic manifestation of lethal midline granuloma. Although less conspicuous, blood vessel invasion and thrombosis were also observed in 62% of obvious lymphomas, raising the possibility that these lesions evolve into a spectrum, in which highgrade histopathologic features are associated with an aggressive clinical course. Diagnostic criteria were established to separate lymphomatoid granulomatosis into three categories based on the content of atypical lymphoid c e k 5 pure, focal lymphoma, and diffuse lymphoma. Moreover, both nasal and pulmonary lesions were shown to progress from low-grade to highgrade histopathology over time. Both lethal midline granuloma and lymphomatoid granulomatosis may extend to involve tissues outside the respiratory tract, including lymph nodes, skin, and the central nervous system. In this context, the term angiocentric immunoproliferative lesion (AIL) was proposed to include both lethal midline granuloma/polymorphic reticulosis and lymphomatoid granulomatosis6 and guidelines for grading were set forth (grade I: polymorphic infiltrate with minimal necrosis, few large atypical lymphoid cells, and small lymphocytes lacking nuclear irregularities; grade 11: cytologic atypia of small lymphocytes, scattered large atypical lymphoid cells, and intermediate amounts of necrosis; and grade 111: lymphoma, either diffuse mixed, large cell, or immunoblastic, with prominent necrosis). Immunologic characterization of AIL shows that the large atypical cells consistently express CD2, frequently CD3 and HLA-DR antigens, and variably CD4, CD5, CD7, and CD25, but not B-lineage differentiation antigen^.'“^