Section 3 -

Lymphomatoid Granulomatosis Elaine S. Jaffe National Cancer Institute Bethesda, MD

Lymphomatoid granulomatosis (LYG) was described as an atypical angiocentric and angiodestructive lymphoproliferative disease involving the lungs as well as other extranodal sites, mainly the kidneys, upper respiratory system, skin and central nervous system. [1] The authors encountered this condition in the course of their studies of Wegener's granulomatosis (WG) with which it was distinguished. Liebow et al. coined the term LYG to note the similarity of this condition to WG, both in terms of pulmonary involvement and multisystem disease. However, granulomatous inflammation, a frequent feature of WG, was not seen in LYG, which they considered to be principally an angiodestructive disorder composed of "lymphoreticular cells." Since its description nearly 25 years ago, LYG has been an enigma. It shares some clinical and histopathologic features with nasal and nasal-type T/NK cell lymphoma, also termed angiocentric lymphoma, and at times was even considered part of a common clinicopathologic entity, "angiocentric immunoproliferative lesion" (AIL). [2] Because of the predominance of T-cells within the lesions, and the frequent cytologic atypia, it had been thought to be a form of T-cell lymphoma. [3] Other authors, in an attempt to unify the spectrum of clinical and histologic findings in LYG (and perhaps other related conditions), proposed that LYG was not a discrete clinicopathologic entity, but a histologic response that could be encountered in the course of many diseases, including lymphoma. [4] The mysterious nature of LYG has been largely resolved in recent years. As initially suggested by Liebow et al., it is linked to the Epstein-Barr virus (EBV). [5] In LYG EBV is localized to B-lymphocytes, although in some cases the number of EBV-infected cells is small [6]. Moreover, EBV-positive B-cells may not be present in all sites, and some of the vascular lesions may be mediated by the effects of chemokines upregulated by EBV expression [7]. In the lesions identified in the lung and other sites, most of the infiltrating lymphoid cells are secondary or reactive, presumably recruited in response to EBV. These cells are mainly T-lymphocytes. [8] The histologic grade of LYG is based on the respective proportions of the EBV-infected B-cells, which may be monoclonal or oligoclonal, and the reactive component. [6, 9] An associated immunodeficiency appears to be an intrinsic component of LYG, since in most cases clinical and laboratory evidence of defective T-cell function can be identified. [9] Moreover, the observed host response is ineffective in eradicating the EBV-infected clone(s). The nature of the angiodestructive aspect of LYG is also beginning to be understood. Vascular destruction is probably multifactorial. It involves both angioinvasion by infiltrating cells, mainly reactive T-lymphocytes, as well as chemokine mediated vascular damage, induced by EBV. Therefore, EBV lies at the heart of LYG, and is intrinsically linked to all aspects of its pathogenesis and pathophysiology. Histopathology, Immunopathology & Genetic Features LYG produces nodular mass lesions in most affected organs, most commonly the lung, kidney, liver, and brain. [10] Other sites of involvement include upper respiratory tract, skin, and gastrointestinal tract. The nodules have a polymorphous cellular composition, composed of lymphocytes, plasma cells, immunoblasts, and scattered histiocytes. Neutrophils, eosinophils, or well-formed granulomas are usually infrequent or absent. The large cells, which are of B-cell origin, may show atypia with large pleomorphic nuclei and prominent nucleoli, resulting in a Reed-Sternberg-like appearance. Occasionally, these cells can be multinucleated, further mimicking Hodgkin's disease. [11] The majority of the lymphocytes are T-cells, a finding that originally led to the supposition that LYG was a type of T-cell lymphoma. CD4-positive cells exceed CD8-positive cells, but both are present. The smaller lymphocytes may show slight irregularity or atypia, but lack convincing cytologic features of malignancy. The larger immunoblasts or pleomorphic large cells usually express B-cell markers such as CD20 or CD79a, which can be detected in paraffin sections. [12, 13] However, immunoglobulin expression is difficult to demonstrate, and therefore determination of monotypic or polytypic light chain expression in tissue sections is usually not possible. One must resort to molecular studies to examine the clonality of the B-cells in these lesions. The large atypical cells may be CD30-positive; EBV has been shown to upregulate CD30 in B-cells and B-cell-lines. However, CD15 is negative, a finding useful in excluding the diagnosis of Hodgkin's disease. Plasma cells are variable in number. They are usually polyclonal, but in rare cases may be monoclonal for light chain expression. [9] The diagnosis should not be based solely on a perivascular or interstitial pattern of lymphoid infiltration. Larger lesions, and lesions of higher histologic grade, usually show prominent parenchymal necrosis. The necrotic lesions differ from those seen in WG, and lack neutrophils or abundant nuclear debris. The coagulative aspect of the necrosis suggests a vascular basis. Blood vessels may be affected in one of two ways. Lymphocytes, mainly T-cells, may show direct vascular invasion. This infiltration, a manifestation of the angioinvasion of LYG, can cause infarct-like tissue necrosis. However, in some lesions there appears to be primary vascular damage. [7] EBV latent membrane protein (LMP) can cause upregulation of both IP-10 and Mig, which have been shown to cause endothelial and vascular damage, including fibrinoid necrosis. Patients with LYG also have increased serum levels of IP-10, suggesting that these chemokines may even act at distant sites. [7] Skin lesions are seen in approximately 50% of patients. Most commonly these are subcutaneous or dermal nodules, often with necrosis [14]. However, a more non-specific maculopapular rash may also be seen. EBV is not commonly identified in the skin lesions, and their pathogenesis is not clear-cut. They usually do not appear to represent direct involvement by the primary lymphoproliferative process. The WHO classification proposes a grading scheme for LYG. [15] In Grade I lesions EBV-positive cells as detected by EBER in situ hybridization are infrequent (<5/ HPF). LMP-1 stains many fewer cells than in situ hybridization and in some cases may be entirely negative. Grade II lesions more frequent EBER-positive cells, usually in the range of 5-20/ HPF. Grade III lesions contain numerous EBER+ cells (> 25/ hpf in most areas of the section, or >50/hpf seen focally), most of which are large and atypical. They be dispersed, or in some cases sheet out. Immunomodulatory approaches are recommended only for patients with Grade I or II disease, whereas at this point in time, Grade III patients should be treated for diffuse large B-cell lymphoma. [9] Grading should be based on a dominant mass lesion outside the skin. In addition, histologic grade may vary over time or from site to site. In general, histologic grade increases in patients with relapsed disease. Lesions in the central nervous system are also often of high histologic grade. Clonal IgH gene rearrangements are more often identified in high grade lesions. [16] Clonality can also be identified by investigation of terminal repeat regions of EBV. Interestingly, we have encountered a number of instances of LYG in which distinct B-cell clones have been identified in different sites in the same patient, either at the same point in time, or consecutively. This finding is analogous to post-transplant associated lymphoproliferative disease (PTLPD), in which clonal expansion of B-cells may take place in a variety of sites. Clonal rearrangement of T-cell receptor genes has been negative. The exact pathogenesis of Grade I lesions devoid of EBV-positive B-cells is still uncertain [13]. These lesions could result from a very exuberant host response to a rare or evanescent infected B-cell. We have seen instances of LYG in which EBV-positive cells could not be detected in the primary Grade I pulmonary lesion; however, subsequently EBV-positive cells became numerous with time and histologic progression [9]. One must also consider the possibility that some cases of pulmonary LYG might have a different pathogenesis, although evidence for a clonal T-cell origin has not yet been provided. Finally, other forms of lymphoma, including T-cell lymphomas, may involve the lung, and may be mistaken for or mimic typical LYG. Epidemiology and Immune Status Although most cases of LYG occur in apparently otherwise healthy patients, it sporadically occurs in patients with known underlying immunodeficiencies. These include primary immunodeficiencies, such as Wiskott-Aldrich Syndrome and Human Immunodeficiency Virus (HIV) and Human T-cell Leukemia Virus infection (HTLV-1), as well as secondary immunodeficiencies associated with chemotherapy and organ transplantation (Reviewed in [2]. Such epidemiological associations suggested that all patients with LYG may have some degree of immune compromise, and provided the basis for assessing immune function in those patients who did not have an antecedent history of immunodeficiency. Studies have found evidence of impaired humoral and cell mediated responses to EBV, suggesting that patients with LYG cannot effectively control EBV induced B-cell proliferation either because of a generalized immunodeficiency or a more specific EBV-related immunodeficiency. [17] Differential Diagnosis The clinical presentations of LYG and Wegener's granulomatosis can be very similar; both frequently present with constitutional symptoms, bilateral nodular pulmonary infiltrates, renal lesions, and skin involvement. [18] However, Wegener's granulomatosis classically involves the upper respiratory tract, which is rarely affected in LYG, and the pathogenesis and histological findings are quite different. Pathologically, Wegener's granulomatosis is characterized by a necrotizing vasculitis of small arteries and veins with granuloma formation. Renal lesions show a focal and segmental glomerulitis, rather than the nodular infiltrates characteristic of LYG. Although both LYG and nasal-type NK/T-cell lymphoma (NK/TCL) are EBV-associated and typically extranodal. The sites of involvement differ, with NK/TCL involving upper airways, midline facial structures, gastrointestinal tract and skin; pulmonary involvement is not common. Pathophysiologically, LYG appears to belong within the spectrum of EBV-lymphoproliferative diseases, and shares a number of histological and clinical similarities with post-transplant lymphoproliferative disease (PTLD). [19] Both occur in immunocompromised patients and may contain polyclonal, oligoclonal and/or monoclonal proliferations of EBV infected B-cells. However, the immune response appears to be different. In LYG, a distinguishing pathologic feature is an exuberant angiocentric T-cell reaction with necrosis, whereas in typical PTLD, most cells are plasmacytoid B cells with fewer T cells. In addition, LYG is associated with a necrotizing vasculitis that is rarely seen in PTLD. [20] Based on these pathological differences, Wilson et al proposed the term T-cell rich EBV lymphoproliferative disease (T-RELD) for LYG, and T-cell poor EBV lymphoproliferative disease (T-PELD) for PTLD. [9] Bibliography Liebow AA, Carrington CRB, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol 1972;3:457-558. Jaffe ES, Lifford EH, Margolick JB, Longo DL, Fauci AS. Lymphomatoid granulomatosis and angiocentric lymphoma: a spectrum of post-thymic T-cell proliferations. Semin Resp Med 1989;10:167-72. Nichols PW, Koss M, Levine AM, Lukes RJ. Lymphomatoid granulomatosis: a T-cell disorder. Am J Med 1982;72:467-71. Pisani RJ, DeRemee RA. 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