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A 57-Year-Old Woman With Persistent Cough and Pulmonary NodulesWoman With Persistent Cough and Pulmonary Nodules FREE TO VIEW

Jeffrey Albores, MD; Michael C. Fishbein, MD; Tisha Wang, MD
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Drs Albores and Wang), David Geffen School of Medicine at UCLA, and UCLA Pathology & Laboratory Medicine (Dr Fishbein), Los Angeles, CA.

Correspondence to: Jeffrey Albores, MD, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, 37-131 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095; e-mail: jalbores@mednet.ucla.edu


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


Chest. 2014;145(5):1162-1165. doi:10.1378/chest.13-1950
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A 57-year-old white woman presented to our pulmonary clinic with a 4-month history of a chronic nonproductive cough. The cough was persistent and severe. She noted shortness of breath and diffuse chest pain that occurred only during coughing. She previously used an angiotensin-converting enzyme inhibitor, but it had been stopped 2 months prior. She also reported fatigue, night sweats, and a 9 kg (20-lb) weight loss. She was a lifelong nonsmoker and denied any postnasal drip, gastroesophageal reflux symptoms, or history of asthma. She tried treatment with a proton pump inhibitor, azithromycin, benzonatate, and albuterol without significant relief. Results from a previous direct flexible laryngoscopy procedure were unremarkable.

Physical Examination Findings

Physical examination revealed the following vital signs: BP, 100/60 mm Hg; pulse rate, 90 beats/min; respiration rate, 18 breaths/min; and no fever. Oxygen saturation was 98% on room air. The rest of the physical examination was unremarkable except for a persistent cough throughout the visit. The patient’s lungs were clear to auscultation bilaterally.

Diagnostic Studies

Pulmonary function test and chest radiograph findings were normal. A chest CT scan revealed diffuse, ill-defined centrilobular nodularity (Fig 1) as well as splenomegaly. Fungal serologic test results for coccidioides, Cryptococcus, and histoplasma were negative. The patient underwent fiber-optic bronchoscopy with BAL and transbronchial biopsy of the right middle and right lower lobes. BAL cultures were negative for pathogens. The transbronchial biopsy specimens revealed a focal increase in cellularity, with cells filling the alveolar spaces on a low-power view. Higher magnification showed infiltrating neoplastic cells, and immunohistochemical stains were positive for leukocyte common antigen (CD45) and CD20.

Figure Jump LinkFigure 1. Chest CT scans showing diffuse ill-defined centrilobular nodularity.Grahic Jump Location
What is the diagnosis?
Diagnosis: Pulmonary diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma. Pulmonary involvement is extremely rare. We present a case of a pulmonary DLBCL presenting as chronic cough with B symptoms and an abnormal CT scan revealing diffuse centrilobular nodularity.

Pulmonary lymphoma can be defined as primary when it affects one or both lungs (parenchyma, trachea, bronchi, or any combination) without any evidence of extrapulmonary involvement at diagnosis or during the subsequent 3 months. Primary pulmonary non-Hodgkin’s lymphoma (NHL) is extremely rare and accounts for 0.4% of all lymphomas. The most common primary pulmonary lymphoma is mucosa-associated lymphoid tissue lymphoma, which represents 70% to 90% of all primary pulmonary NHL. Pulmonary DLBCL is even more rare and occurs in only 10% of cases of primary pulmonary NHL. Transformation from mucosa-associated lymphoid tissue lymphoma to DLBCL may also occur in some cases.

Information regarding the clinical and pathologic features of pulmonary DLBCL is scant, but in general, this condition parallels the course of lymphomas arising at other sites. Risk factors for primary pulmonary NHL have not been defined. Patients are mostly asymptomatic, but symptomatic cases present with respiratory symptoms such as cough and dyspnea. Lung involvement can manifest as nodules, diffuse ground glass opacities, and cavitary and endobronchial lesions.

Diagnosis of primary pulmonary lymphoma requires histopathologic examination of lung tissue. Fiber-optic bronchoscopy with transbronchial biopsy is the most frequently used technique but often has a low diagnostic yield. BAL does not provide a complete morphologic analysis for an accurate diagnosis of lymphoma, but samples from BAL can be improved through molecular and immunophenotypic study. Flow cytometry can be performed on BAL samples and on lymphocytes recovered from small fresh-tissue samples. Flow cytometry can provide relevant information by revealing the presence of clonal B-cell populations as well as by demonstrating an antigenic profile compatible with the diagnosis. Primary pulmonary lymphoma may present with hilar or mediastinal lymphadenopathy. In such cases, a safe, minimally invasive technique, such as endobronchial ultrasound transbronchial needle biopsy, is typically used to sample an accessible lymph node. If tissue from transbronchial biopsy is insufficient, there is no lymph node to sample by endobronchial ultrasound, or BAL is inconclusive, then open-lung biopsy or video-assisted thoracoscopic surgery is performed as a definitive diagnostic modality to obtain lung tissue. Most prior case reports included diagnoses of pulmonary DLBCL from open-lymph node biopsy, transbronchial biopsy of a known lung mass, and open thoracotomy with wedge resection of intralobar lung. There have been no reports of a diagnosis made through blind transbronchial biopsies for imaging showing diffuse nodularity.

Histopathologic examination with immunohistochemical staining is necessary to confirm the diagnosis of DLBCL. Tumor cells usually are diffusely positive for leukocyte common antigen (CD45), indicating that these cells are lymphoid cells, and CD20, indicating that these cells are B lymphocytes (Fig 2). Epstein-Barr Virus (EBV) detection is crucial in the diagnosis of DLBCL. The 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues recognizes a new entity associated with EBV infection in the immunocompetent host, namely EBV-positive DLBCL of the elderly. It occurs in patients aged > 50 years without any known immunodeficiency or prior lymphoma. The prognosis of age-related EBV-positive DLBCL is inferior to EBV-negative DLBCL.

Figure Jump LinkFigure 2. Transbronchial biopsy specimen. A, Low-power view showing focal increase in cellularity with cells filling alveolar spaces (arrows) (hematoxylin-eosin, original magnification × 20). B, High magnification showing infiltrating neoplastic cells (hematoxylin-eosin, original magnification × 200). C, Immunohistochemical stain showing positive results for leukocyte common antigen (CD45) (original magnification × 100). D, Immunostain showing positive results for CD20 (original magnification × 200). The cells also showed positive results for CD79a, PAX5, BCL6, and MUM-1 and negative results for CD10 and C-MYC.Grahic Jump Location

The treatment of primary pulmonary lymphomas is not clearly established. The therapeutic approach should be based on biologic features, such as histology, stage, and performance status. Treatment strategies include surgery, chemotherapy, or chemotherapy followed by radiotherapy. Anthracycline-based chemotherapy in conjunction with an anti-CD20 monoclonal antibody appears to be the optimal therapeutic strategy in patients with pulmonary DLBCL. Negative prognostic indicators include stage IV disease, nongerminal center immunophenotype, primary extranodal DLBCL, and elevated serum lactate dehydrogenase (LDH) level.

Histopathology from transbronchial biopsy specimens of the right middle and right lower lobes revealed DLBCL nongerminal center immunophenotype with negative in situ hybridization studies for EBV (Fig 2). A bone marrow biopsy specimen was negative for lymphomatous involvement, and PET scan revealed fludeoxyglucose activity within the enlarged spleen. Splenomegaly was noted on the repeat abdominal examination. Splenomegaly with positive PET scan findings would indicate that the patient had Ann Arbor stage IV pulmonary NHL. Her serum LDH level was elevated at 811 U/L (normal, 91-223 U/L).

The patient was referred to oncology, and chemotherapy with EPOCH-R (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone, and rituximab) was initiated. Within 3 days of her initial chemotherapy, the patient had resolution of her cough, and at the time of her third cycle of chemotherapy, repeat imaging with PET/CT scan revealed a near-complete response to treatment. She completed six cycles of chemotherapy within a 5-month period. Despite negative prognostic factors in this patient (stage IV disease, nongerminal center immunophenotype, primary extranodal DLBCL, and an elevated LDH level), she had an excellent response to chemotherapy and resolution of the debilitating cough.

  • 1. Pulmonary lymphoma should be considered in the differential diagnosis of chronic cough with B symptoms in the context of compatible chest CT scan findings.

  • 2. Pulmonary DLBCL is extremely rare.

  • 3. Histopathologic examination with immunohistochemical staining is necessary to confirm the diagnosis of DLBCL.

  • 4. Prompt treatment should be initiated for this aggressive form of malignancy.

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: This work was performed at the Ronald Reagan UCLA Medical Center. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Fiche M, Caprons F, Berger F, et al. Primary pulmonary non-Hodgkin’s lymphomas. Histopathology. 1995;26(6):529-537. [CrossRef] [PubMed]
 
Habermann TM, Ryu JH, Inwards DJ, Kurtin PJ. Primary pulmonary lymphoma. Semin Oncol. 1999;26(3):307-315. [PubMed]
 
Ferraro P, Trastek VF, Adlakha H, Deschamps C, Allen MS, Pairolero PC. Primary non-Hodgkin’s lymphoma of the lung. Ann Thorac Surg. 2000;69(4):993-997. [CrossRef] [PubMed]
 
Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J. 2002;20(3):750-762. [CrossRef] [PubMed]
 
Chilosi M, Zinzani PL, Poletti V. Lymphoproliferative lung disorders. Semin Respir Crit Care Med. 2005;26(5):490-501. [CrossRef] [PubMed]
 
Zinzani PL, Martelli M, Poletti V, et al; Italian Society for Hematology; Italian Society of Experimental Hematology; Italian Group for Bone Marrow Transplantation. Practice guidelines for the management of extranodal non-Hodgkin’s lymphomas of adult non-immunodeficient patients. Part I: primary lung and mediastinal lymphomas. A project of the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2008;93(9):1364-1371. [CrossRef] [PubMed]
 
Wróbel T, Dzietczenia J, Prochorec-Sobieszek M, Mazur G, Piwkowski P. Primary pulmonary diffuse large B-cell lymphoma. Am J Hematol. 2012;87(1):107-108. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Chest CT scans showing diffuse ill-defined centrilobular nodularity.Grahic Jump Location
Figure Jump LinkFigure 2. Transbronchial biopsy specimen. A, Low-power view showing focal increase in cellularity with cells filling alveolar spaces (arrows) (hematoxylin-eosin, original magnification × 20). B, High magnification showing infiltrating neoplastic cells (hematoxylin-eosin, original magnification × 200). C, Immunohistochemical stain showing positive results for leukocyte common antigen (CD45) (original magnification × 100). D, Immunostain showing positive results for CD20 (original magnification × 200). The cells also showed positive results for CD79a, PAX5, BCL6, and MUM-1 and negative results for CD10 and C-MYC.Grahic Jump Location

Tables

Suggested Readings

Fiche M, Caprons F, Berger F, et al. Primary pulmonary non-Hodgkin’s lymphomas. Histopathology. 1995;26(6):529-537. [CrossRef] [PubMed]
 
Habermann TM, Ryu JH, Inwards DJ, Kurtin PJ. Primary pulmonary lymphoma. Semin Oncol. 1999;26(3):307-315. [PubMed]
 
Ferraro P, Trastek VF, Adlakha H, Deschamps C, Allen MS, Pairolero PC. Primary non-Hodgkin’s lymphoma of the lung. Ann Thorac Surg. 2000;69(4):993-997. [CrossRef] [PubMed]
 
Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J. 2002;20(3):750-762. [CrossRef] [PubMed]
 
Chilosi M, Zinzani PL, Poletti V. Lymphoproliferative lung disorders. Semin Respir Crit Care Med. 2005;26(5):490-501. [CrossRef] [PubMed]
 
Zinzani PL, Martelli M, Poletti V, et al; Italian Society for Hematology; Italian Society of Experimental Hematology; Italian Group for Bone Marrow Transplantation. Practice guidelines for the management of extranodal non-Hodgkin’s lymphomas of adult non-immunodeficient patients. Part I: primary lung and mediastinal lymphomas. A project of the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2008;93(9):1364-1371. [CrossRef] [PubMed]
 
Wróbel T, Dzietczenia J, Prochorec-Sobieszek M, Mazur G, Piwkowski P. Primary pulmonary diffuse large B-cell lymphoma. Am J Hematol. 2012;87(1):107-108. [CrossRef] [PubMed]
 
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