Answer: Low grade B-cell lymphoma

Histology: The lesion in this biopsy is that of an exquisitely interstitial infiltrate composed of small, bland-appearing lymphocytes. The infiltrate involves interalveolar and interlobular septa and extends to involve the pleural surface. The lymphoid cells in the infiltrate are small and round with bland nuclear features and minimal mitotic activity. Admixed with the lymphoid infiltrate are numerous non-necrotizing granulomas. The air spaces are essentially uninvolved, although there are focal accumulations of intralveolar macrophages. The lesion is diffuse and involves lung parenchyma away from the airways. The diagnostic feature in this biopsy is that of extensive permeation of the interlobular septa and their vessels by the lymphoid infiltrate. This permeative involvement of the septal vasculature has been termed “lymphangitic spread”. In this particular biopsy the infiltrate is composed almost purely of small lymphocytes. In other cases, however, there may be an admixture of plasma cells or other lymphoid elements, especially in biopsies taken from the edge of an area of infiltrate. The “lymphangitic” pattern of septal permeation is therefore an extremely important diagnostic feature. In most cases, immuno or molecular studies are not necessary in formulation of the proper diagnosis, and, in fact, these studies may be misleading in section specimens taken from the advancing edge of the infiltrate where a mixture of cells may be present. The presence of interstitial granulomas may provide confusion with either sarcoid or maybe extrinsic allergic alveolitis (hypersensitivity pneumonitis). In neither of these entities would there be the intense lymphoid infiltrate seen here. Granulomas in pulmonary lymphoproliferative process are usually poorly formed and not the characteristic “naked” granulomas of sarcoid and the absence of foci of bronchiolitis obliterans organizing pneumonia (BOOP) would favor a lymphoproliferative process over that of extrinsic allergic alveolitis.

Discussion: The differential diagnosis of small lymphocytic proliferations of the lung involves primarily the separation of low-grade lymphoma from reactive processes. Lymphoid interstitial pneumonia (LIP) is also a diffuse pulmonary disorder characterized by an interstitial infiltrate of mature lymphocytes. There is generally a variable admixture of plasma cells and other mononuclear cells. LIP is commonly associated with other conditions including HIV-AIDS (especially in children), Sjogren’s syndrome, chronic active hepatitis and other autoimmune disorders. In contradistinction to low-grade lymphoma, the infiltrate of LIP lacks the prominent “lymphangitic” septal permeation of lymphoma. It is important to remember that neither the presence of germinal centers nor of a polymorphous infiltrate can effectively distinguish between LIP and low-grade lymphomas. Both germinal centers and poorly formed granulomas may be seen in either process. Other reactive lymphoid processes in the lung include reactive (BALT) lymphoid hyperplasia/follicular bronchiolitis and pseudolymphoma. Both LIP and follicular bronchiolitis are seen in patients with immunodeficiencies including HIV-AIDS and the distinction between these two entities is sometimes blurred. Pseudolymphoma in the lung may focally be similar to LIP, or low-grade lymphoma, but it usually causes an isolated mass density rather than diffuse infiltrate. It may be preferable to use the term “inflammatory pseudotumor” for this lesion. Since pseudolymphoma can be considered to represent the sequel to healing inflammatory or infectious processes, one would expect to see scarring in the process. The mass is usually nodular and partially obliterates the lung architecture. Scarring with dense collagen is most prominent in the center of the lesion, but necrosis is absent. There is an associated polymorphous inflammatory cell infiltrate and numerous germinal centers may be present. It would not be uncommon to see evidence of organizing pneumonia in the surrounding parenchyma. On occasion, a prominent lymphoid infiltrate in association with interstitial remodeling and scarring leads to the question of LIP or low-grade lymphoma in cases of idiopathic interstitial fibrosis. In these instances, the lymphoid infiltrate is prominent, but not as dramatic as that seen in LIP or lymphoma, and the distinction can usually be made on clinical and morphologic grounds.