Lung Biopsy Interpretation
Case 8 -
Lymphomatoid granulomatosis (LYG)
Anna-Luise A. Katzenstein & Jeffrey L. Myers
This 24 year old man presented with fever and nonhealing erosive skin lesions on his lower
extremities. Chest x-ray revealed bilateral circumscribed opacities. Skin biopsy was nondiagnostic and
he underwent open lung biopsy.
Case 8 - Figure 1 - Low magnification photomicrograph illustrating a zone of necrosis bounded by a densely cellular infiltrate.
Case 8 - Figure 2 - High magnification view illustrating a polymorphic lymphocytic infiltrate that includes isolated large atypical cells with coarsely clumped chromatin and prominent nucleoli. Large atypical cells represent the population of neoplastic EBV-infected B cells.
Case 8 - Figure 3 - Photomicrograph demonstrating a transmural infiltrate of lymphoid cells involving a pulmonary artery.
At low magnification, this biopsy shows a centrally necrotic nodule. Although at first blush the
nodule resembles a granuloma, closer inspection of the cellular infiltrate comprising the periphery
demonstrates a mixture of predominantly lymphocytes with variable numbers of associated plasma cells and
histiocytes. The lymphocytic infiltrate shows mainly small and intermediate size cells with scattered
large atypical cells. The atypical cells are most numerous near the necrotic center and are
characterized by enlarged, pleomorphic nuclei with coarse chromatin and prominent enlarged nucleoli. The
polymorphic lymphoid infiltrate shows a distinctive predilection to infiltrate vessel walls, resulting in
narrowing of the lumens of affected vessels.
Liebow and colleagues first described pulmonary lymphomatoid granulomatosis (LYG) as a distinct
clinicopathologic entity in 1972. It was defined as an angiocentric lymphoproliferative process with
prominent pulmonary involvement. As originally described, the diagnosis hinged on recognition of a
characteristic histologic triad: 1) polymorphic lymphoid infiltrate, 2) angiitis, and 3)
"granulomatosis". The most distinctive feature was the presence of a polymorphic mononuclear cell
infiltrate composed of small lymphocytes, plasma cells, and variable numbers of large immunoblasts.
Angiitis was a consistent finding characterized by transmural infiltration of the walls of arteries and
veins by mononuclear cells. The term "granulomatosis" was used to describe the necrosis occurring within
the lymphoid nodules rather than true granuloma formation.
The intimate relationship between LYG and malignant lymphoma was well recognized from the outset. The
original authors balked at designating the condition lymphoma because most patients lacked nodal disease,
the liver and spleen were rarely involved, occasional patients spontaneously recovered, and the
polymorphic nature of the infiltrate defied existing histological criteria for diagnosis of lymphoid
malignancy. Recognition and study of extranodal lymphomas over the last two decades has explained some
of the "deviant characteristics" of LYG and there is now little doubt regarding the neoplastic nature of
LYG has characteristic clinical features. Males are affected more often than females by a ratio of
2-3:1; patients usually present in the fifth or sixth decade of life. Respiratory symptoms, most
commonly cough, occur in the majority of patients and are frequently associated with systemic complaints
such as fever and weight loss. Extrathoracic manifestations are common and include skin involvement in
37% and central or peripheral nervous system involvement in 30% of patients. Chest roentgenograms
typically show bilateral discrete rounded nodules which may show cavitation. Intrathoracic adenopathy is
rare as is peripheral adenopathy. Traditionally, LYG-lymphoma has carried a poor prognosis with a
cumulative mortality of 57% in the two largest retrospective series. Recent experience suggests that
aggressive chemotherapy substantially improves survival. Wilson and colleagues reported success in 4
patients using interferon- a 2b as a single agent, and suggested further investigation of
antiviral/immunomodulating drugs in this condition.
Historically many examples of LYG were thought to represent T-cell lymphomas. Prior to 1994, most
cases of LYG had been analyzed using frozen section immunostaining techniques and showed a mature T-cell
phenotype, characteristic of so-called peripheral T-cell lymphomas. An aberrant T-cell phenotype had
been demonstrated in a few cases, although clonal rearrangements of the T-cell receptor gene had been
documented only rarely and never in lung tissue. Importantly, clonal T-cell receptor gene rearrangements
were usually not identified, even in some cases with aberrant T-cell phenotypes and in one with a
cytogenetically abnormal clone.
Most cases of LYG are now thought to represent EBV-related B-cell lymphoproliferative disorders with
an exuberant reaction of non-neoplastic T lymphocytes. Guinee and colleagues demonstrated a minor
population of EBV-infected CD20 positive B lymphocytes in biopsies of LYG, and a monoclonal pattern of
immunoglobulin heavy chain gene rearrangements was found in two thirds. They concluded that most cases
of LYG involving the lung represent examples of EBV related B-cell lymphoproliferative disorders with a
prominent component of reactive T lymphocytes. We reported our own experience with 17 open lung biopsies
from patients with LYG and observed a predominance of T lymphocytes in all cases. Our findings differed
somewhat from Guinee et al., however, in that a minor population of CD20-positive large B lymphocytes was
identified in only 11 cases; immunoglobulin light chain restriction was demonstrated in 4 of these, and
immunoglobulin gene rearrangements in another. Staining for CD20 was absent in the remaining 6 cases;
however, the large atypical lymphoid cells stained for T-cell lineage specific antibodies in 3 of these
cases. We concluded that some cases of LYG are B-cell lymphomas analogous to so-called "T-cell rich
B-cell lymphomas" while others may represent T-cell lymphomas. Several authors have now confirmed the
unique "T-cell rich B-cell" phenotype that characterizes the majority of cases of LYG and have
demonstrated that most represent monoclonal or oligoclonal proliferations of B lymphocytes (see Table).
Table 1: Lymphomatoid Granulomatosis -- an EBV-related B-cell Lymphoma
| ||N ||CD20+ lge cells ||EBV+ cells ||clonal|
|Guinee et al. ||10 ||10 ||10 ||6|
|Myers et al.|| 17 ||11 ||10 ||5|
|McNiff et al. ||4 ||4 ||3 ||4|
|Nicholson et al. ||7 ||7 ||4 ||3|
|Wilson et al. ||4 ||4 ||4 ||2|
|TOTAL ||42 ||36 ||31 ||20|
A number of other studies of LYG have shown a link to EBV infection. Liebow and colleagues theorized
an etiologic role for EBV and even suggested that ". . . studies analogous to those that have led to the
identification of a virus associated with Burkitt's lymphoma should be performed in lymphomatoid
granulomatosis." Katzenstein and Peiper identified EBV viral DNA sequences in lung biopsies of LYG using
the polymerase chain reaction. Southern blotting and in-situ hybridization techniques have also
demonstrated EBV sequences in LYG, particularly those cases with cytologically malignant large lymphoid
cells. Although Medeiros and colleagues using double labeling techniques suggested that EBV infected
cells represented neoplastic T-cells, subsequent studies by Guinee et al. demonstrated EBV genomes in
CD20 positive B lymphocytes. In our own study we demonstrated nuclear labeling for EBV RNA in 10 of 11
cases with CD20-positive B cells, and the staining was confined to the population of large B
lymphocytes. Nuclear labeling for EBV RNA was absent in 6 cases lacking CD20-positive large cells.
The most appropriate terminology for LYG remains problematic. None of the classification schemes
currently employed for malignant lymphomas have a suitable nosological category for LYG. As a result
several synonyms have been proposed to replace the term lymphomatoid granulomatosis. The currently
proposed WHO classification of hematopoetic and lymphoid neoplasms applies the term, "diffuse large
B-cell lymphoma, lymphomatoid granulomatosis-type." Jaffe previously coined the term angiocentric immunoproliferative lesion (AIL) to encompass a spectrum of
lymphoproliferative disorders ranging from low grade lesions of uncertain histogenesis (grade I AIL) to
high grade angiocentric lymphomas (grade III AIL). Katzenstein and Askin suggested the term lymphomatoid granulomatosis-lymphoma, which has the advantages of emphasizing that
LYG is a malignant neoplasm while preserving the historical context of this unique clinicopathological
syndrome and separating it from other forms of malignant lymphoma. Using the term malignant lymphoma, angiocentric [mixed small and large cell, or large cell] type,
with a comment concerning phenotype if appropriate data is available, may be the most direct method for
communicating the neoplastic and aggressive nature of LYG. Whatever terminology one prefers, including
in some fashion the term LYG for descriptive purposes may be useful to emphasize the unique clinical and
pathological features of this lesion.
The differential diagnosis of LYG-lymphoma in lung biopsy specimens includes mainly Wegener's
granulomatosis and other forms of malignant lymphoma. Wegener's granulomatosis differs from LYG-lymphoma
in that the cellular infiltrate is composed of acute and chronic inflammatory cells and the vasculitis
consists of focal vessel wall necrosis rather than transmural infiltration by lymphoid cells. Other
forms of malignant lymphoma, including Hodgkin's disease and non-Hodgkin's lymphomas, can involve the
lung and show histologic features that overlap with LYG-lymphoma. Recognition of Hodgkin's disease
requires identification of diagnostic Reed-Sternberg cells as it does in extrapulmonary sites.
Distinguishing LYG-lymphoma from other types of non-Hodgkin's lymphomas is more problematic. The term
LYG-lymphoma should be reserved for those cases with the histologic triad initially outlined by Dr.
Liebow et al: a polymorphic lymphoid infiltrate, vascular infiltration, and necrosis. It is the
presence of a polymorphic infiltrate in at least a portion of the tumor that is most useful in
distinguishing LYG from other forms of pulmonary lymphoma. Vascular infiltration alone is an
insufficient criterion because it can occur in other types of malignant lymphoma. Ultimately, of course,
recognition of LYG as a distinct clinicopathologic entity requires careful correlation of biopsy findings
with clinical and radiographic data.
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