Marginal Zone B-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MZBCL/MALT) Type
Marginal zone B-cell lymphoma of MALT type is a low-grade extranodal malignant lymphoma that is comprised predominantly of small B-lymphoid cells with the phenotypic features of marginal zone B-cells. Patients are usually older adults, although it may occur in children, particularly in those infected with the human immunodeficiency virus (HIV) another type of immunodeficiency. There is no striking sex predominance. Although most MALT lymphomas are suspected to arise as a result of chronic antigen stimulation (e.g., Helicobacter pylori in gastric MALT lymphoma), no specific etiologic agent has been found for pulmonary MZBCL. Most patients present wit non-specific pulmonary complaints or a mass less than 5 cm. or multiple masses (particularly with more sensitive studies) in an otherwise asymptomatic patient. Hilar lymphadenopathy is usually not present. A subset of patients may have a history of a previous or synchronous MALT at another site.

Histologically, larger neoplasms show a central mass associated with obliteration of alveolar spaces, with peripheral tracking along lymphatic pathways, i.e., around airways, along vessels, and into interlobular septa and the visceral pleura. Smaller lesions may have a completely intact alveolar network. Bronchial infiltration often is associated with the formation of lymphoepithelial lesions, seen somewhere within the neoplasm into about 90% of cases (although not pathognomonic). Often, one sees reactive germinal centers, either within the neoplasm, adjacent to the bronchovascular structures, or at the periphery. Typically, the neoplastic population is present adjacent to and replacing expanded marginal zones of the germinal centers. Cytologically, the predominant cell is a small lymphocyte, which may be round and regular or lymphoplasmacytic, but more often has some irregularities of the nuclear membrane and possesses an abundant clear rim of cytoplasm (so-called monocytoid cells). Scattered plasma cells may be present, as well as small regular lymphocytes, and variable numbers of large, transformed cells. If these large cells form sheets, the diagnosis of a composite diffuse large B-cell lymphoma should be considered. In addition, occasional multinucleated giant cells or even well-formed non-caseating granulomas may be seen. Additional histologic features may include giant lamellar bodies (eosinophilic whorled bodies), sclerosis, or amyloid deposition, phenomena probably reflecting the indolent nature of the underlying process.

The neoplastic cells have the immunophenotypic features of marginal zone B-lymphocytes, expressing the pan-B markers CD20, PAX5, and CD79a. Characteristic of marginal zone B-cells, they are typically CD5-, CD10-, CD23-, BCL6-, BCL1/cyclin D1-, and BCL2+. CD43 is expressed in up to 50% of cases. Nuclear expression of BCL10 may be found in those cases with a t(11;18) or a t(1;14) (see below). Light chain restriction may be demonstrated when there is a significant plasmacytic component to the neoplasm, seen in about 25% of cases. Stains for follicular dendritic cells (e.g., CD21, CD23, and CD35) can demonstrate not only reactive germinal centers, but also disrupted and partially obliterated follicles that have been colonized and overrun by the neoplasm. Ki-67 is typically below 10-20%, and can also highlight germinal centers. Keratin stains may highlight lymphoepithelial lesions. Appropriate molecular studies show consistent clonality of the immunoglobulin heavy and/or light chain genes. In addition, approximately 25-50% of cases have a t(11;18) (API2-MALT1), about 20% of cases have a trisomy 3, while about 5-10% each have a t(14;18) (involving MALT1, not BCL2, gene), a t(1;14), or trisomy 18.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
The incidence of CLL/SLL presenting in the lung is unknown, since it has so often been confused with MZBCL/MALT in the literature; but it must be uncommon. Lung involvement in CLL/SLL usually occurs in patients with a longstanding history. In the large majority of these cases, the diagnosis is evident, with biopsy typically reserved for those in which concurrent infection is suspected. Patients usually present with progressive cough and/or shortness of breath and have interstitial infiltrates on chest radiographs. Occasionally, patients present with symptoms of endobronchial obstruction. As in other cases of CLL/SLL, patients are usually over 50 years, with a 2:1 M:F ratio. There is usually a lymphocytosis greater than 10 x 10⁹l.

Histologically, there is usually a dense lymphoid infiltrate that follows the bronchovascular bundles and/or a bronchiolocentric distribution, with relative sparing of the rest of the lung parenchyma. Evidence of pseudofollicles (proliferation centers) may be present if the infiltrate very extensive. There may be an accompanying granulomatous reaction, which may appear to be necrotizing. The proliferating cells contain a predominant population of small round lymphocytes, with a mature chromatin pattern, along with scattered large cells with a more vesicular chromatin pattern and evident nucleoli. The presence of sheets of these larger cells would suggest the presence of composite diffuse large B cell lymphoma.

The cells of CLL/SLL are B-lymphocytes, expressing the pan-B cell markers CD20, PAX5, and CD79a. In addition, they show consistent co-expression of CD5, CD43, CD23, and BCL2. They are negative for CD10, BCL6, and BCL1/cyclin D1. Ki-67 is typically below 10-20%. Appropriate molecular studies consistent clonality of the immunoglobulin heavy and/or light chain genes. In addition, about 80% of cases show abnormal karyotypes (which are not typically translocations). Trisomy 12, abnormalities at 13q14, and deletions at 11q22-23, 6q21, or 17p13 are among the more frequent findings.

Mantle Cell Lymphoma
Mantle cell lymphoma is an aggressive incurable malignant lymphoma differentiating toward mantle cells of the follicles. Similar to CLL/SLL, presentation of mantle cell lymphoma is rare, and lung is an unusual site of involvement, even in cases of advanced disease. At low magnification, one may see a diffuse, vaguely nodular, or mantle zone pattern of infiltration. At high magnification, the proliferating cells are monomorphic population of small to intermediate sized lymphoid cells with mild to marked nuclear irregularities and a relatively mature chromatin pattern, without prominent nucleoli. Scattered large cells, such as may be seen in MZBCL/MALT are not seen. There may be scattered epithelioid histiocytes, but aggregations into granulomas are not seen. There is a blastoid subtype, seen in about 10% of cases, in which the cells have either a fine chromatin pattern, resembling lymphoblastic lymphoma, or a more vesicular chromatin pattern, approaching large cell lymphoma. The blastoid cases are usually more aggressive than other cases of mantle cell lymphoma.

The cells of mantle cell lymphoma have a characteristic immunophenotype. Similar to the other small B cell lymphomas, they express the pan-B cell markers CD20, PAX5, and CD79a. They usually (but not always) express CD5 and CD43, BCL2, and BCL1/cyclin D1 expression is seen in about 90% of cases. By flow cytometry, they usually are positive for FMC-7. They are negative for CD10, CD23, and BCL6. Ki-67 usually ranges between 20-50%. Molecular studies show clonality of the immunoglobulin heavy and/or light chain genes. At least 90% of cases have a t(14;18), involving the BCL1 gene.

Follicular Lymphoma
Similar to CLL/SLL and mantle cell lymphoma, presentation of follicular lymphoma in the lung is rare. Typically, there is widespread disease evident clinically, and lung biopsy is being performed to rule out the possibility of infection. Histologically, the follicular pattern characteristic of follicular lymphoma of the lymph node is usually seen in the lung as well. The follicles contain an admixture of small and large cleaved cells (centrocytes), along with variable numbers of large non-cleaved cells (centroblasts). Grading is based upon the number of centroblasts present (grade 1: 0-5 centroblasts per hpf; grade 2: 6-15 per hpf; grade 3:>15 centroblasts per hpf.

The neoplastic cells of follicular lymphoma express the pan-B cell markers CD20, PAX5, and CD79a. In addition, they are typically positive for BCL2 (in contrast to reactive follicles), BCL6, and CD10, and negative for CD5, CD43, and CD23. Stains for follicular dendritic cells may be useful in outlining the follicles. Ki-67 is variable, from 10 to >40%; Ki-67 in reactive follicles is usually much higher. Molecular studies show clonality of the immunoglobulin heavy and/or light chain genes, although it is difficult to identify all cases by PCR (for technical reasons). At least 90% of cases have a t(14;18), involving the BCL2 gene.

Follicular Bronchitis/Bronchiolitis
Follicular bronchitis/bronchiolitis is benign polyclonal disease pattern characterized by nodular lymphoid infiltration of the walls of bronchi and bronchioles and their surrounding peribronchial and peribronchiolar tissues, often with the formation of nodules. It occurs in both children and adults. In children, it is most often associated with immunodeficiency; while in adults, it is usually associated with autoimmune disease and hypersensitivity syndromes. Patients usually present with cough and/or dyspnea. Radiologic studies usually reveal a bilateral peribronchial and interstitial pattern of involvement.

Histologically, one sees nodular aggregates of lymphoid cells, with or without germinal centers. The process is most usually accentuated immediately around the airways but may be present anywhere within the bronchovascular bundle, along the interlobular septa and beneath the pleura. The nodules consist of primary follicles or reactive secondary follicles (germinal centers). Small mature lymphocytes and polyclonal plasma cells are often found surrounding the nodules. Immunohistochemical studies demonstrate that the follicles are comprised of a polyclonal population of B-cells, with BCL2- germinal centers. The surrounding mature lymphocytes are usually CD3+ T cells, and the plasma cells are polytypic. Molecular studies consistently demonstrate a germline configuration of the immunoglobulin heavy and light chain genes. No clonal cytogenetic abnormalities are present.

Lymphocytic Interstitial Pneumonia (LIP)
Lymphocytic interstitial pneumonia (LIP) is a benign polyclonal disease pattern characterized by a diffuse, interstitial lymphoid infiltrate. It is similar to follicular bronchitis/bronchiolitis in many respects, and may represent a more advanced form of the latter disorder. It occurs in both children and adults. In children, it is most frequently associated with AIDS, but it may also be associated with congenital immune deficiencies. In adults LIP is usually associated with autoimmune disease, particularly Sjögren's syndrome. Other conditions associated with LIP in adults include immunodeficiencies, viruses, and drugs. Patients usually present with cough and/or dyspnea. A dysproteinemia--usually hypergammaglobulinemia or, less frequently, hypogammaglobulinemia--is often present. Radiologic studies reveal an interstitial process.

Histologically, the hallmark is an interstitial infiltrate comprised of small mature lymphocytes with variable numbers of plasma cells (more found in non-AIDS patients). There are usually changes of follicular bronchitis/bronchiolitis also present. Germinal centers are present in about 50% of cases, and granulomatous changes—ranging from multinucleated giant cells to well-formed granulomas are also frequently found. Immunohistochemical studies show a mixture of B and T cells, with B cells found in nodules (primary follicles) and germinal centers and T cells present in the intervening areas—with good architectural demarcation between the two components. The plasma cells are polytypic. Molecular studies reveal a germline configuration of the immunoglobulin heavy and light chain genes, and there are no clonal cytogenetic abnormalities.

Nodular Lymphoid Hyperplasia (NLH)
Nodular lymphoid hyperplasia is a mass-like lesion (or several lesions) consisting of a population of reactive lymphoid cells with variable numbers of plasma cells. It is one of the entities that used to be included within the designation of pulmonary pseudotumor. It is a very rare lesion that usually occurs in adults, with a 1.3 M:F ratio. Most cases are discovered as incidental masses on radiologic studies, although non-specific symptoms of cough and/or dyspnea may be present. On radiologic studies, a solitary mass, usually between 2 and 5 cm., is found, although multiple lesions are occasionally present. The mass is usually present in a subpleural location, although there is no true invasion of the pleura seen histologically.

At low magnification, one sees a mass of reactive lymphoid tissue. The most striking finding is the presence of numerous reactive germinal centers. Variable numbers of plasma cells and small mature lymphocytes are seen in the interfollicular areas, which may also show dense fibrosis. Immunohistochemical studies show the follicles and other nodules to be composed of B cells, while the interfollicular areas have a dominant population of T cells along with polytypic plasma cells. Molecular studies reveal a germline configuration of the immunoglobulin heavy and light chain genes, and there are no clonal cytogenetic abnormalities.

Diagnostic Work-up of Small Lymphocytic Proliferations of the Lung
Evaluation of the patient with a possible small lymphocytic proliferation of the lung must start with a complete history and physical, particularly to identify a past history of a lymphoproliferative disorder such as CLL/SLL, mantle cell lymphoma, or follicular lymphoma, as well as an examination of the peripheral blood, which may include flow cytometry analysis to identify a subtle monotypic B-cell population. PCR analysis of alveolar B lymphocytes obtained by bronchoalveolar lavage may also be useful; in particular, the absence of a dominant B-cell clone could help to dismiss invasive investigations of pulmonary lymphoma. Transbronchial biopsy may be useful for bronchial-based lesions, but may not be the best procedure when lymphocytic interstitial pneumonitis is a strong consideration.

The following findings are suggestive of B-cell lymphoma in paraffin section immunohistochemical studies:

1. Light chain restriction of plasma cells or plasmacytoid cells (seen when a prominent plasmacytic component is part of the neoplasm, such as in MZBCL/MALT);
   
   
2. Aberrant co-expression of CD5 (seen in CLL/SLL and almost all cases of MCL);
   
   
3. Aberrant co-expression of CD43 (seen in up to 50% of cases of MZBCL/MALT and almost all cases of CLL/SLL and MCL);
   
   
4. Aberrant co-expression of BCL1/cyclin D1 (seen in >90% of cases of MCL);
   
   
5. Aberrant co-expression of BCL2 in atypical follicular B-cells (seen in 90% of cases of follicular lymphoma;
   
   
6. Significant B cell infiltration outside of follicles, with no demarcation between B and T cell compartments (difficult to apply without experience).

1. Immunoglobulin heavy and/or light chain gene rearrangements found in paraffin sections in about 90% of cases of MZBCL/MALT, CLL/SLL, and MCL, and 80% of cases of follicular lymphoma.
   
   
2. Immunoglobulin heavy and/or light chain gene rearrangements are not found in reactive lesions, particularly if the analysis is repeated (tiny specimens).
   
   
3. PCR may be useful in detecting of t(14;18) of follicular lymphoma, t(11;14) of mantle cell lymphoma and t(11;18), t(14;18), and t(1;14) of MCBCL/MALT.

References

1. Streubel, B, Simonitsch-Klupp, I, Mullauer, L, Lamprecht A, Huber D, Siebert R, Stolte M, Trautinger F, Lukas J, Puspok A, Formanek M, Assanasen T, Muller-Hermelink H-K, Cerroni L, Raderer M, Chott A. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia (2004) 18, 1722-1726.
   
   
2. Zinzani PL, Tani M, Gabriele A, Poletti V., Stefoni V, Alinari L, Musura G, Bonifazi F, Pileri S, Tura S, Baccarani M. Extranodal marginal zone B-cell lymphoma of MALT-type of the lung: single-center experience with 12 patients. Leuk Lymphoma (2003) 44, 821-824.
   
   
3. Remstein E, Kurtin P, Einerson R, Paternoster S, Dewald G. Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1. Leukemia (2004) 18, 156-160.
   
   
4. Kim J, Lee S, Park J, Kim H, Lee S, Park J, Kim K, Kim W, Jung C, Park Y, Im Y, Kang W, Lee M, Park K, Han J, Ko Y. Primary pulmonary non-Hodgkin's lymphoma. Jpn J Clin Oncol (2004) 34, 510-514.
   
   
5. Zompi S, Couderc L, Cadranel J, Antonie M, Epardeau B, Fleury-Feith J, Popa N, Santoli F, Farcet J, Delfau-Larue. Clonality analysis of alveolar B lymphocytes contributes to the diagnostic strategy in clinical suspicion of pulmonary lymphoma. M. Blood (2004) 103, 3208-3215.
   
   
6. Koss M. Malignant and benign lymphoid lesions of the lung. Annals of Diagnostic Pathology (2004) 8, 167-187.
   
   
7. Chernoff A, Rymuza J, Lippmann ML. Endobronchial lymphocytic infiltration. Unusual manifestation of chronic lymphocytic leukemia. Am J Med (1984) 77, 755-759.
   
   
8. Rollins SD, Colby TV. Lung biopsy in chronic lymphocytic leukemia. Arch Pathol Lab Med. (1988) 112, 601-611.
   
   
9. Berkman N, Polliack A, Breuer R, Okon E, Kramer M. Pulmonary involvement as the major manifestation of chronic lymphocytic leukemia. Leuk Lymphoma (1992) 8, 495-499.
   
   
10. Palosaari DE, Colby TV. Bronchiolocentric chronic lymphocytic leukemia. Cancer (1986) 58, 1695-1698.