—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 8 - Lymphomatoid granulomatosis (LYG)

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
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.

Microscopic Description:


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.

Discussion:
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 this lesion.

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.

References

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