Lymphoid Lesions of the Lung

Pathologic Features

Microscopic Findings

Histologically, intrapulmonary lymph nodes appear similar to lymph nodes in other areas of the body. They contain both primary and secondary germinal centers ( Fig. 22.2 ). Histiocytes containing anthracotic pigment are often prominent in nodal sinuses.

Differential Diagnosis

Intrapulmonary lymph nodes are usually histologically distinct and not readily confused with other entities. Metastatic carcinoma should be sought in patients with known lung cancer. Intrapulmonary thymoma and nodular lymphoid hyperplasia may occasionally enter the differential diagnosis. Intrapulmonary thymoma is histologically similar to mediastinal thymoma. Unlike intrapulmonary lymph nodes, thymomas are usually larger (0.5–12 cm) and contain variable mixtures of lymphocytes and epithelial cells, usually subdivided into lobules by fibrous bands. If needed, immunohistochemical staining for cytokeratin will highlight admixed epithelial cells and readily discriminate between these two entities. Although nodular lymphoid hyperplasia shares some histologic features with intrapulmonary lymph nodes, lesions of nodular lymphoid hyperplasia are usually larger (2–4 cm), lack the architecture of a lymph node, contain variable amounts of fibrosis, and may efface the underlying pulmonary parenchyma.

Pathologic Features

Microscopic Findings

Follicular bronchitis/bronchiolitis consists of lymphoid follicles, often with prominent germinal centers, in a peribronchiolar or peribronchial distribution ( Fig. 22.4A ). The hyperplastic follicles often reside between bronchioles and pulmonary arteries and can compress the bronchiolar lumens ( Fig. 22.4B ). Lymphocytes may be present in the adjacent bronchiolar epithelium. Lymphoid follicles may also be present in a lymphangitic distribution along the interlobular septa and beneath the pleura ( Fig. 22.4A ). These findings can also be present in patients with LIP (see later), and there are cases where both of these patterns occur concurrently.

Ancillary Studies

Differential Diagnosis

The differential diagnosis of follicular bronchiolitis includes LIP, low-grade lymphoma of BALT, pulmonary involvement by chronic lymphocytic leukemia, and nodular lymphoid hyperplasia. Although LIP may show peribronchial and peribronchiolar lymphoid follicles (eg, focal areas of follicular bronchiolitis), this feature is usually overshadowed by the conspicuous diffuse chronic interstitial inflammatory infiltrate that defines this pattern. Although there may be focal involvement of alveolar septa by a chronic interstitial inflammatory infiltrate in follicular bronchiolitis, it is not a prominent feature. Nonetheless, there is substantial overlap between the histologic patterns and clinical conditions associated with follicular bronchiolitis and LIP, and in some cases, the distinction is somewhat arbitrary. Low-grade lymphoma of BALT may have follicles with germinal center formation. However, these lymphomas usually contain confluent areas of monomorphous lymphocytes without germinal centers. Lymphoid cells may permeate cartilage and cause effacement of other normal structures. Similarly, pulmonary involvement by chronic lymphocytic leukemia is distinguished by a monomorphous infiltrate of small lymphocytes with a lymphatic distribution. In contrast to follicular bronchiolitis, nodular lymphoid hyperplasia usually presents as a well-demarcated mass consisting of a confluent proliferation of germinal centers admixed with sheets of interfollicular plasma cells.

Pathologic Features

Microscopic Findings

LIP is characterized by a dense, interstitial, predominantly mononuclear cell infiltrate that diffusely expands alveolar septa ( Fig. 22.6A ). The infiltrate consists primarily of lymphocytes, histiocytes, and plasma cells ( Fig. 22.6B ). In some cases, there are germinal centers along bronchovascular bundles and septa. The histologic features in these cases overlap with the pattern of follicular bronchiolitis. Other findings occasionally encountered include poorly formed granulomas and multinucleated giant cells, and secondary alveolar changes can include collections of proteinaceous fluid, scattered mononuclear inflammatory cells, and foamy macrophages or giant cells. In later lesions, there may be variable amounts of fibrosis and even honeycombing, ultimately resulting in end-stage lung disease.

Ancillary Studies

Differential Diagnosis

The differential diagnosis of LIP is broad. It includes all disorders in which there is a prominent lymphoid infiltrate: low-grade lymphoma of BALT, pulmonary involvement by chronic lymphocytic leukemia, angioimmunoblastic lymphadenopathy, nodular lymphoid hyperplasia, follicular bronchiolitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonitis (NSIP), and in chronic forms, usual interstitial pneumonitis. Pulmonary involvement by low-grade lymphoma or chronic lymphocytic leukemia is distinguished from LIP by the monomorphism of the lymphoid infiltrate. Infiltration of bronchial cartilage and pleura may be present in low-grade lymphoma of BALT, but these are absent in LIP. In cases where morphologic distinction is difficult, immunohistochemical stains and polymerase chain reaction (PCR) analysis for IgH heavy chain rearrangement can be helpful. Interstitial lymphocytes in low-grade lymphomas of BALT and chronic lymphocytic leukemia consist predominantly of B-cells that express CD20. Kappa or lambda light chain restriction can sometimes be demonstrated by immunohistochemical staining of associated plasma cells. PCR analysis for IgH chain gene rearrangements will frequently show a clonal rearrangement.

Angioimmunoblastic lymphadenopathy can occasionally involve the lung in a diffuse pattern. However, this disorder is usually suspected based on the clinical and radiographic features, which include generalized lymphadenopathy combined with hepatosplenomegaly, autoimmune hemolytic anemia, and skin rash. Nodular lymphoid hyperplasia is readily distinguished from LIP by its presentation as a well-demarcated mass, as opposed to the diffuse interstitial involvement of LIP. Although follicular bronchiolitis may show focal extension of the lymphoid cells into the peribronchiolar interstitium, the diffuse interstitial involvement seen in LIP is lacking. Nonetheless, many cases of LIP have associated lymphoid follicles with germinal centers along bronchioles and, in occasional cases, the histologic features overlap, making the distinction between the two somewhat subjective. Hypersensitivity pneumonitis can be distinguished from LIP by its patchy peribronchiolar accentuation; patchy, poorly formed granulomas; and occasional foci of organizing pneumonia. Although interstitial lymphocytic infiltrates are characteristic of cellular NSIP, the density of the lymphoid infiltrate is less than LIP. Nonetheless, NSIP and LIP may be difficult to distinguish morphologically, and many cases of LIP in the older literature would now be reclassified as NSIP. Given their similar etiologies and associations, LIP, in fact, may be considered just a more exuberantly cellular expression of NSIP. Finally, particularly in immunocompromised patients (eg, those with AIDS), infections should be considered as potential etiologies for LIP. In these patients, evidence of EBV, cytomegalovirus, Pneumocystis jirovecii, and mycobacteria should be sought by special stains and/or molecular testing.

Pathologic Features

Microscopic Findings

Nodular lymphoid hyperplasia is a well-demarcated nodule consisting of aggregates of lymphoid follicles with reactive germinal centers and sheets of interfollicular plasma cells, most often in a subpleural location ( Fig. 22.7A ). Plasma cells may contain Russell bodies. Foci of interfollicular fibrosis may be present and may focally efface the underlying pulmonary parenchyma. Significantly, Dutcher bodies, bronchial or pleural permeation, lymphoepithelial lesions, and amyloid are absent. Resected hilar or mediastinal nodes, when present, show reactive lymphoid hyperplasia.

Ancillary Studies

Differential Diagnosis

The main entity in the differential diagnosis of nodular lymphoid hyperplasia is MALT (BALT) lymphoma. Other entities to be considered include LIP, follicular bronchiolitis, inflammatory pseudotumor, and plasmacytoma. Nodular lymphoid hyperplasia can usually be distinguished from MALT lymphoma by a number of findings ( Table 22.2 ). MALT lymphomas tend to show infiltration of pleura and bronchial cartilage, features that should not be seen with nodular lymphoid hyperplasia. Lymphangitic spread is usually prominent in MALT lymphomas but mild and focal in nodular lymphoid hyperplasia. Lymphoepithelial lesions are absent in nodular lymphoid hyperplasia but variably present in BALT lymphoma. Likewise, intranuclear inclusions (Dutcher bodies) are absent in nodular lymphoid hyperplasia but variably present in MALT lymphoma. Immunohistochemical staining for kappa and lambda light chain restriction shows a polyclonal pattern in nodular lymphoid hyperplasia but a monoclonal pattern in most cases of MALT lymphoma. Staining of lymphocytes in lymphoepithelial lesions for CD43 and CD20 can be found in low-grade lymphomas of MALT but not nodular lymphoid hyperplasia. IgG4-positive plasma cells may be increased in pulmonary nodular lymphoid hyperplasia but not in cases of MALT lymphoma. Additionally, immunoglobulin heavy chain gene rearrangements can be identified in most cases of MALT lymphoma but are not present in nodular lymphoid hyperplasia. Recent studies have suggested that plasmacytoma is a form of MALT lymphoma. Unlike nodular lymphoid hyperplasia, it consists of a monomorphous population of plasma cells that show light chain restriction that can be detected by immunohistochemistry.

Nodular lymphoid hyperplasia is usually easily distinguished from LIP and follicular bronchiolitis. The latter two entities typically involve the lung in a diffuse manner, as opposed to the discrete mass seen in nodular lymphoid hyperplasia. Nodular lymphoid hyperplasia can be distinguished from inflammatory pseudotumor (inflammatory myofibroblastic tumor) of the lung by the absence of an associated myofibroblastic or fibrohistiocytic spindle cell proliferation.

Pathologic Features

Microscopic Findings

Histologic features of IgG4-related disease involving the lung vary. Generally, affected patients have fibroinflammatory masses ( Fig. 22.8A ). These have a characteristic morphology consisting of a lymphohistiocytic inflammatory infiltrate with numerous admixed plasma cells accompanied by fibrosis in a lymphangitic distribution along the pleura, interlobular septa, and bronchovascular bundles ( Fig. 22.8B ). Intimal endothelial inflammation often affects both arteries and veins ( Fig. 22.8C ). A subset of cases of other disease patterns, such as the plasma cell–rich variant of inflammatory pseudotumor, grade I LYG, pulmonary hyalinizing granuloma, and pulmonary nodular lymphoid hyperplasia, show an increase in IgG4-positive plasma cells and are postulated to potentially represent, in some cases, different morphologic expressions of IgG4-related disease.

Ancillary Studies

An elevated serum level of IgG4 is identified in 80% to 90% of patients with pulmonary involvement by IgG4-related disease.

Differential Diagnosis

Cases of grade I LYG, plasma cell–rich inflammatory pseudotumor, pulmonary hyalinizing granuloma, and pulmonary nodular lymphoid hyperplasia may have an increased number of IgG4-positive plasma cells on immunohistochemistry. The significance of these findings is not completely clear. They may represent alternative morphologic expressions of IgG4-related disease or, alternatively, a nonspecific increase in IgG4-positive plasma cells occurring through some other mechanism. Higher-grade lesions of LYG (grade II and III) are easily distinguished by the presence of atypical cells, which stain positively for EBV by in situ hybridization techniques. Inflammatory myofibroblastic tumor is in the differential of plasma cell–rich variants of inflammatory pseudotumors. These are true neoplasms with a fascicular proliferation of spindled cells. The number of associated IgG4-positive plasma cells is usually lower as well.

A pattern resembling NSIP may be present in some patients with IgG4-related sclerosing disease. Biopsies show a diffuse interstitial lymphoplasmacytic infiltrate, which expands alveolar septa, is present along bronchovascular bundles, and may involve the pleura. The infiltrate also involves small arterioles and venules, which may show obliterative arteritis and phlebitis. Abundant IgG4-positive plasma cells are present on immunohistochemical staining. This histologic pattern generally corresponds to those cases with the radiographic findings of ground-glass infiltrates. It is distinguished from idiopathic cases of NSIP by the increased numbers of IgG4-positive plasma cells present.

Erdheim-Chester disease and pulmonary involvement by Rosai-Dorfman disease are similar to pulmonary involvement by IgG4-related disease in that they have a prominent lymphangitic distribution. Erdheim-Chester disease, however, generally lacks the marked lymphoplasmacytic inflammatory background and vascular inflammation found in IgG4-related disease. An increase in IgG4-positive plasma cells is not identified. Moreover, in contrast to cases of Erdheim-Chester disease, characteristic radiographic findings in long bones are absent. Some cases of Rosai-Dorfman disease do show an increase in IgG4-positive plasma cells and can pose difficulty in the differential diagnosis. Rosai-Dorfman disease typically presents clinically with massive bilateral cervical lymphadenopathy. It is characterized by an infiltrate of large histiocytes with eosinophilic cytoplasm containing entrapped lymphocytes. This latter feature has been termed emperipolesis. Emperipolesis may be present focally in pulmonary involvement by IgG4-related disease but is usually not as prominent as in Rosai-Dorfman disease. Nonetheless, the similarity in some of the histologic and immunohistochemical features between Rosai-Dorfman disease and IgG4-related disease has prompted some authors to suggest these disorders overlap.