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A 54-Year-Old Man Referred With Nonresolving PneumoniaNonresolving Pneumonia FREE TO VIEW

Julie Catteeuw, MD; Coenraad F. N. Koegelenberg, MBChB, PhD; Johannes W. Bruwer, MBChB; Gerhard Sissolak, MD, PhD; Leocardea Schroeter, MD; Nooroudien Mohamed, MBChB, MMed; Elvis M. Irusen, MBChB, PhD, FCCP
Author and Funding Information

From the Division of Pulmonology (Drs Catteeuw, Koegelenberg, Bruwer, and Irusen) and the Division of Hematology (Dr Sissolak), Department of Medicine, and the Division of Anatomical Pathology (Drs Schroeter and Mohamed), Department of Pathology, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa.

CORRESPONDENCE TO: Julie Catteeuw, MD, Division of Pulmonology, Department of Medicine, Stellenbosch University, PO Box 19063, Tygerberg, 7505, Cape Town, South Africa; e-mail: Julie.catteeuw@ugent.be


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(3):e92-e96. doi:10.1378/chest.13-2790
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A 54-year-old man was referred with nonresolving pneumonia. He had been treated for community-acquired pneumonia 6 weeks earlier. He reported grade 2 dyspnea, malaise, and a nonproductive cough. He had also experienced three episodes of minimal hemoptysis but denied weight loss, fever, or any other constitutional symptoms. He was a nonsmoker and was being treated for dyslipidemia.

His general clinical examination was unremarkable, with a Karnofsky performance status scale of 80. His respiratory examination yielded crackles and bronchial breathing in the left lower zone.

A repeat chest radiograph revealed an unchanged infiltrate, and a CT scan of the chest confirmed extensive consolidation of the left lower lobe (Fig 1) as well as a contralateral lesion in the superior segment of the right lower lobe. Blood investigations were all noncontributory.

Figure Jump LinkFigure 1  The patient’s CT scan of the chest revealed dense consolidation involving mostly the left upper lobe, with some involvement of the apical segment of the right lower lobe. The infiltrates were both PET scan avid (not shown). There is no pleural effusion.Grahic Jump Location

As it is known that the timing of radiologic resolution of pneumonia varies with patient age and the presence of an underlying lung disease, we considered this as a nonresolving pneumonia, because radiologic clearance of the pneumonia in this patient should be expected in 4 to 6 weeks. Many of the causes of nonresolving pneumonia were considered, such as neoplasms (eg, adenocarcinoma with lepidic growth, lymphoma), TB and fungal infections, inflammatory disorders such as cryptogenic organizing pneumonia, eosinophilic pneumonias, systemic vasculitis, and drug-induced lung diseases. We decided to perform flexible bronchoscopy. Abnormal mucosa (with erythema and swelling) in the left lower lobe bronchus was noted, and numerous bronchial washings and brushings were obtained for routine microbiology, acid-fast bacilli staining, GeneXpert (a cartridge-based test to detect DNA sequences specific for Mycobacterium tuberculosis and rifampicin resistance by polymerase chain reaction [PCR]), culture for TB, and cytology. Transbronchial biopsies were sent for routine histology and microbiology. None of the microbiologic samples yielded any positive results. Normal bronchial cells with some chronic inflammatory cells but without malignancy were present on cytology.

The histology of the tissue showed an infiltrate of small lymphoid cells with irregular nuclei, condensed chromatin, and moderate amounts of pale to clear cytoplasm (Fig 2). The cells were CD20, CD43, and bcl2 positive and did not coexpress CD5, CD10, CD23, and cyclin D1. Myocyte nuclear factor did not demonstrate the presence of lymphoepithelial lesions. The clonality of this lymphoid infiltrate could not be confirmed with κ and λ staining, but the PCR test showed IgH gene rearrangement. Translocation (11,18), analyzed by fluorescence in situ hybridization, was not present in the tissue sample.

Figure Jump LinkFigure 2  The bronchial wall is diffusely effaced by an infiltrate of small lymphoid cells (monomorphic population) with irregular nuclei (hematoxylin and eosin, magnification × 100).Grahic Jump Location

PET CT scan demonstrated intense fluorodeoxyglucose (FDG) uptake in both parenchymal lesions (maximum standardized uptake value, 12.44 in the left lower lobe and 4.19 right lower lobe), with uptake in a right paratracheal node (maximum standardized uptake value, 4.39). There were no signs of disease in other sites.

What is the diagnosis?
Diagnosis: Primary mucosa-associated lymphoid tissue lymphoma of the lung

No evidence of Helicobacter pylori or other infections was found at gastroscopy, and the patient’s bone marrow was clear of any infiltration. He, thus, conformed to stage IIA in the Ann Arbor classification.

The term mucosa-associated lymphoid tissue (MALT) lymphoma was first described by Isaacson and Wright in 1983.1-5 MALT is a lymphoid tissue specialized in mucosal defense.6 MALT is usually not detectable in the normal lung but can develop during chronic antigenic stimulation and may undergo secondary lymphomatous transformation arising from marginal zone B cells.6 In the latest World Health Organization classification, MALT lymphomas belong to the marginal-zone lymphomas but are distinguished from the nodal and splenic forms by their different clinical behavior and cytogenetic characteristics (Table 1).5-8

Table Graphic Jump Location
TABLE 1  ] Morphologic, Immunohistochemical, and Molecular Features of MALT Lymphoma

+ and − refer to immunohistochemical stain positivity and negativity. MALT = mucosa-associated lymphoid tissue; MIB = mindbomb E3 ubiquitin protein ligase 1; PCR = polymerase chain reaction. (Adapted from Bacon et al.14)

Primary lymphoma of the lung is a rare entity (< 1% of primary malignant lung tumors, < 1% of all lymphomas) that originates from the lung, in contrast to secondary pulmonary lymphomas. Two types of primary lymphoma of the lung exist: low-grade and high-grade pulmonary B-cell lymphoma. MALT lymphoma constitutes > 90% of the low-grade pulmonary B-cell lymphoma and tends to disseminate late and only after many local relapses.1,3,8,9

MALT lymphoma is most frequently localized to the GI tract, and H pylori is known as one of the causative pathogens.2,6,10 Even at other sites, chronic infections are believed to be associated with MALT lymphoma. However, an association between a specific pathogen and lung MALT lymphoma has not been established.5,6,8,11 Some evidence indicates an association between chronic antigenic stimulation from smoking or autoimmune diseases, such as systemic lupus erythematosus, and pulmonary MALT lymphomas.5,12 Although the initial lymphoid hyperplasia is driven by physiologic antigenic stimulation, additional oncogenic events, such as chromosomal translocations leading to constitutive activation of signaling pathways, occur during the progression of disease that ultimately result in antigen-independent lymphoproliferation.4

Clinical Discussion

Symptoms and physical signs are nonspecific and contribute little to the diagnosis. At least one-third of the patients have no symptoms.5,7,13 Chronic fatigue, low-grade fever, weight loss, cough, and shortness of breath can be present. Recurrent respiratory infections may occur. No sex-related or racial differences in MALT distribution are known, and the age of onset is usually around 50 to 60 years.5,6,9

Radiologic Discussion

There are no specific changes seen on chest radiograph or CT scan. MALT lymphoma can present as patchy opacities or mass-like consolidation (in up to 68%) and multiple nodules in > 50% of the cases.12,13 Dilated airways within the consolidated lung and pleural effusion have also been described. Primary lung lymphoma can only be designated as such in the absence of extrapulmonary lymph node involvement at diagnosis or during the subsequent 3-month surveillance.1,6,13

A unique and challenging issue is staging. This should be assessed with a CT scan of the thorax, abdomen, and pelvis; examination of the GI tract with biopsies, including identification of H pylori status; and bone marrow biopsy. Some authors also suggest MRI of the salivary and lacrimal glands.3,4,6 However, as there is no difference in progression-free survival and overall survival between the localized and disseminated cases, the value of such an exhaustive staging evaluation has been questioned.4

The value of PET scanning in the evaluation of dissemination is uncertain. MALT lymphoma, with indolent growth, has little FDG uptake.4,8 Borie at al8 suggest that FDG uptake might be site specific, with sensitivity of 50% to 89% and 83% to 100% for stomach and lung involvement, respectively.

Pathologic Discussion

Most cases can be diagnosed by minimally invasive procedures, including transbronchial biopsy and CT scan-guided transthoracic biopsy.14 There is no uniform protocol regarding the indications for surgery.8,13

The role of BAL has as yet not been established.15,16 BAL has proven useful in isolated cases; its use is infrequently mentioned in large published series.6,7 A WBC count with plasma cells of 40% and lymphocytes of 17% with prominence of CD19/20 positivity may suggest MALT lymphoma.13 B-cell alveolitis is particularly valuable when its clonal nature can be demonstrated by the detection of Ig gene clonal rearrangements using molecular biology-based methods.6,7

MALT lymphomas are low-grade B-cell lymphomas composed of small- to medium-sized lymphocytes (centrocyte-like cells) that have irregular nuclear contours and abundant cytoplasm (Table 1).5,6,14 The World Health Organization definition describes MALT lymphomas as an extranodal lymphoma composed of morphologically heterogeneous small B cells, including marginal zone cells, cells resembling monocytoid cells, small lymphocytes, and scattered immunoblasts. There is plasma cell differentiation in a proportion of cases. The infiltrate is in the marginal zone of reactive B-cell follicles and extends into the interfollicular region. In epithelial tissues, neoplastic cells typically infiltrate the epithelium, forming lymphoepithelial lesions.

The immunohistochemistry is practically identical to that of nonneoplastic marginal- zone B cells, showing CD19, 20, and CD79a positivity, but CD10, cyclin D1, and CD5 negativity.6,14,15,17 No specific immunohistochemical marker has yet been identified for MALT lymphoma, but evaluation of a panel of immunostains is necessary for assessment of the architecture of the lymphoid infiltrate as well as for the exclusion of other lymphomas. CD5 and cyclin D1 positivity is seen in mantle cell lymphoma, whereas CD10 and bcl6 positivity is observed in follicular lymphoma. CD23 helps to distinguish from B-cell chronic lymphocytic leukemias. In approximately 50%, there is also aberrant coexpression of CD43 by these small B cells, a phenotype strongly suggestive of lymphoma.14 If histology and immunohistochemistry are insufficient to make a diagnosis, demonstrating B-cell clonality by PCR-based analysis of Ig gene rearrangements can contribute to the diagnosis.14

Detection of recurrent genetic abnormalities by fluorescence in situ hybridization should be encountered in the diagnostic workup, as pulmonary MALT lymphoma displays a specific genetic aberration, the t (11,18)(q21;q21), resulting in the API2/MALT1fusion transcript, in approximately 50%.3,14 The prognostic significance of genetic changes in nongastric MALT lymphomas is largely unknown.14

Bone marrow biopsy is crucial, as invasion is seen in 20% to 30% of patients and apparently even more frequently in patients with MALT lymphoma not involving the GI tract.6,18 The only laboratory tests that may be of use are serum electrophoresis and immunoelectrophoresis. Monoclonal gammopathy (IgM in 80%) can be found in 20% to 60% of cases.

Primary lung MALT lymphoma remains a rare and poorly understood entity, with an indolent course and a reasonably favorable prognosis. The diagnosis and staging can be challenging.

The current treatment regimen of choice is surgery for patients with limited disease and chemotherapy (with or without antibody treatment) for patients with advanced disease. Inappropriately aggressive therapy that results in serious injury or long-term disability is a serious medicolegal hazard in the management of MALT lymphomas, as the potential to spontaneously regress should be taken into account in the treatment plan.3,11 The study of Troch et al3 even suggested that patients with pulmonary MALT lymphoma might not require immediate therapy following diagnosis.

Chemotherapy for MALT lymphomas has not been extensively studied. The traditional monotherapy regimens used for MALT lymphomas have included chlorambucil, cyclophosphamide, or fludarabine. In addition, standard combination regimens, such as cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP), have been used successfully, but some studies suggest no higher response rates than single-agent regimens.5,8 The best indication for chemotherapy is bilateral or extrapulmonary involvement, relapse, or progression. Better progression-free survival is observed with chlorambucil when compared with cyclophosphamide or anthracyclin.8 The anti-CD20 monoclonal antibody rituximab has been reported to achieve remissions in patients with gastric MALT lymphomas.11 Radiotherapy is rarely used in primary lung MALT lymphoma.5,6,19 The use of H pylori eradication has not been proven in lung MALT lymphoma.2 Our patient was referred to a medical oncologist and opted for rituximab-CHOP.

MALT lymphoma has a favorable outcome, with a 5-year overall survival of 85% or longer than 10 years.3,4 Dissemination at diagnosis, unlike most other malignancies, does not affect prognosis or survival.2-4,8,20

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology. 1987;11(5):445-462. [CrossRef] [PubMed]
 
Grünberger B, Wöhrer S, Streubel B, et al. Antibiotic treatment is not effective in patients infected with Helicobacter pylori suffering from extragastric MALT lymphoma. J Clin Oncol. 2006;24(9):1370-1375. [CrossRef] [PubMed]
 
Troch M, Streubel B, Petkov V, Turetschek K, Chott A, Raderer M. Does MALT lymphoma of the lung require immediate treatment? An analysis of 11 untreated cases with long-term follow-up. Anticancer Res. 2007;27(5B):3633-3637. [PubMed]
 
Kahl B, Yang D. Marginal zone lymphomas: management of nodal, splenic, and MALT NHL. Hematology Am Soc Hematol Educ Program. 2008;2008(1):359-364. [CrossRef]
 
Verma VJ, Jain S, Singhal S, et al. Primary pulmonary mucosa-associated lymphoid tissue lymphoma in a patient with acquired immune deficiency syndrome. Respir Care. 2011;56(7):1046-1049. [CrossRef] [PubMed]
 
Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J. 2002;20(3):750-762. [CrossRef] [PubMed]
 
Kim JH, Lee SH, Park J, et al. Primary pulmonary non-Hodgkin’s lymphoma. Jpn J Clin Oncol. 2004;34(9):510-514. [CrossRef] [PubMed]
 
Borie R, Wislez M, Thabut G, et al. Clinical characteristics and prognostic factors of pulmonary MALT lymphoma. Eur Respir J. 2009;34(6):1408-1416. [CrossRef] [PubMed]
 
Kocatürk CI, Seyhan EC, Günlüoğlu MZ, et al. Primary pulmonary non-Hodgkin’s lymphoma: ten cases with a review of the literature. Tuberk Toraks. 2012;60(3):246-253. [CrossRef] [PubMed]
 
Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175-1176. [CrossRef] [PubMed]
 
Bilici A, Seker M, Ustaalioglu BB, Canpolat N, Salepci T, Gumus M. Pulmonary BALT lymphoma successfully treated with eight cycles weekly rituximab: report of first case and F-18 FDG PET/CT images. J Korean Med Sci. 2011;26(4):574-576. [CrossRef] [PubMed]
 
Wislez M, Cadranel J, Antoine M, et al. Lymphoma of pulmonary mucosa-associated lymphoid tissue: CT scan findings and pathological correlations. Eur Respir J. 1999;14(2):423-429. [CrossRef] [PubMed]
 
Parissis H. Forty years literature review of primary lung lymphoma. J Cardiothorac Surg. 2011;6:23-31. [CrossRef] [PubMed]
 
Bacon CM, Du MQ, Dogan A. Mucosa-associated lymphoid tissue (MALT) lymphoma: a practical guide for pathologists. J Clin Pathol. 2007;60(4):361-372. [CrossRef] [PubMed]
 
Kido T, Yatera K, Noguchi S, et al. Detection of MALT1 gene rearrangements in BAL fluid cells for the diagnosis of pulmonary mucosa-associated lymphoid tissue lymphoma. Chest. 2012;141(1):176-182. [CrossRef] [PubMed]
 
Poletti V, Romagna M, Gasponi A, Baruzzi G, Allen KA. Bronchoalveolar lavage in the diagnosis of low-grade, MALT type, B-cell lymphoma in the lung. Monaldi Arch Chest Dis. 1995;50(3):191-194. [PubMed]
 
Park KH, Kwon SS, Chung MH, et al. A case of pulmonary MALT lymphoma arising from lymphocytic interstitial pneumonitis. Tuberc Respir Dis (Seoul). 2012;73(2):115-121. [CrossRef] [PubMed]
 
Thieblemont C, Berger F, Dumontet C, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000;95(3):802-806. [PubMed]
 
Goda JS, Gospodarowicz M, Pintilie M, et al. Long-term outcome in localized extranodal mucosa-associated lymphoid tissue lymphomas treated with radiotherapy. Cancer. 2010;116(16):3815-3824. [CrossRef] [PubMed]
 
Raderer M, Wöhrer S, Streubel B, et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol. 2006;24(19):3136-3141. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1  The patient’s CT scan of the chest revealed dense consolidation involving mostly the left upper lobe, with some involvement of the apical segment of the right lower lobe. The infiltrates were both PET scan avid (not shown). There is no pleural effusion.Grahic Jump Location
Figure Jump LinkFigure 2  The bronchial wall is diffusely effaced by an infiltrate of small lymphoid cells (monomorphic population) with irregular nuclei (hematoxylin and eosin, magnification × 100).Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Morphologic, Immunohistochemical, and Molecular Features of MALT Lymphoma

+ and − refer to immunohistochemical stain positivity and negativity. MALT = mucosa-associated lymphoid tissue; MIB = mindbomb E3 ubiquitin protein ligase 1; PCR = polymerase chain reaction. (Adapted from Bacon et al.14)

References

Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology. 1987;11(5):445-462. [CrossRef] [PubMed]
 
Grünberger B, Wöhrer S, Streubel B, et al. Antibiotic treatment is not effective in patients infected with Helicobacter pylori suffering from extragastric MALT lymphoma. J Clin Oncol. 2006;24(9):1370-1375. [CrossRef] [PubMed]
 
Troch M, Streubel B, Petkov V, Turetschek K, Chott A, Raderer M. Does MALT lymphoma of the lung require immediate treatment? An analysis of 11 untreated cases with long-term follow-up. Anticancer Res. 2007;27(5B):3633-3637. [PubMed]
 
Kahl B, Yang D. Marginal zone lymphomas: management of nodal, splenic, and MALT NHL. Hematology Am Soc Hematol Educ Program. 2008;2008(1):359-364. [CrossRef]
 
Verma VJ, Jain S, Singhal S, et al. Primary pulmonary mucosa-associated lymphoid tissue lymphoma in a patient with acquired immune deficiency syndrome. Respir Care. 2011;56(7):1046-1049. [CrossRef] [PubMed]
 
Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J. 2002;20(3):750-762. [CrossRef] [PubMed]
 
Kim JH, Lee SH, Park J, et al. Primary pulmonary non-Hodgkin’s lymphoma. Jpn J Clin Oncol. 2004;34(9):510-514. [CrossRef] [PubMed]
 
Borie R, Wislez M, Thabut G, et al. Clinical characteristics and prognostic factors of pulmonary MALT lymphoma. Eur Respir J. 2009;34(6):1408-1416. [CrossRef] [PubMed]
 
Kocatürk CI, Seyhan EC, Günlüoğlu MZ, et al. Primary pulmonary non-Hodgkin’s lymphoma: ten cases with a review of the literature. Tuberk Toraks. 2012;60(3):246-253. [CrossRef] [PubMed]
 
Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175-1176. [CrossRef] [PubMed]
 
Bilici A, Seker M, Ustaalioglu BB, Canpolat N, Salepci T, Gumus M. Pulmonary BALT lymphoma successfully treated with eight cycles weekly rituximab: report of first case and F-18 FDG PET/CT images. J Korean Med Sci. 2011;26(4):574-576. [CrossRef] [PubMed]
 
Wislez M, Cadranel J, Antoine M, et al. Lymphoma of pulmonary mucosa-associated lymphoid tissue: CT scan findings and pathological correlations. Eur Respir J. 1999;14(2):423-429. [CrossRef] [PubMed]
 
Parissis H. Forty years literature review of primary lung lymphoma. J Cardiothorac Surg. 2011;6:23-31. [CrossRef] [PubMed]
 
Bacon CM, Du MQ, Dogan A. Mucosa-associated lymphoid tissue (MALT) lymphoma: a practical guide for pathologists. J Clin Pathol. 2007;60(4):361-372. [CrossRef] [PubMed]
 
Kido T, Yatera K, Noguchi S, et al. Detection of MALT1 gene rearrangements in BAL fluid cells for the diagnosis of pulmonary mucosa-associated lymphoid tissue lymphoma. Chest. 2012;141(1):176-182. [CrossRef] [PubMed]
 
Poletti V, Romagna M, Gasponi A, Baruzzi G, Allen KA. Bronchoalveolar lavage in the diagnosis of low-grade, MALT type, B-cell lymphoma in the lung. Monaldi Arch Chest Dis. 1995;50(3):191-194. [PubMed]
 
Park KH, Kwon SS, Chung MH, et al. A case of pulmonary MALT lymphoma arising from lymphocytic interstitial pneumonitis. Tuberc Respir Dis (Seoul). 2012;73(2):115-121. [CrossRef] [PubMed]
 
Thieblemont C, Berger F, Dumontet C, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000;95(3):802-806. [PubMed]
 
Goda JS, Gospodarowicz M, Pintilie M, et al. Long-term outcome in localized extranodal mucosa-associated lymphoid tissue lymphomas treated with radiotherapy. Cancer. 2010;116(16):3815-3824. [CrossRef] [PubMed]
 
Raderer M, Wöhrer S, Streubel B, et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol. 2006;24(19):3136-3141. [CrossRef] [PubMed]
 
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