The Role of Infectious Agents in B-cell Lymphomas
Moderators: Dr. Miguel A. Piris and Dr. Steven H. Swerdlow
Section 3 -
Elaine S. Jaffe
National Cancer Institute
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.  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
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).
 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.  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. 
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).
 In LYG EBV is localized to
B-lymphocytes, although in some cases the number of EBV-infected cells is small . 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 . 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.  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
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. 
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
Histopathology, Immunopathology & Genetic Features
LYG produces nodular mass lesions in most affected organs, most commonly the lung, kidney, liver, and
brain.  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. 
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.
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. 
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. 
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. 
Skin lesions are seen in approximately 50% of patients. Most commonly these are subcutaneous or
dermal nodules, often with necrosis . 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.  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.  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.  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 .
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 . 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 . 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. 
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.  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
 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.  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
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