Primary pulmonary lymphomas are uncommon, representing

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1 GENERAL THORACIC Primary Pulmonary Lymphoma Brian B. Graham, MD, Douglas J. Mathisen, MD, Eugene J. Mark, MD, and Ronald W. Takvorian, MD Departments of Thoracic Surgery, Pathology, and Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts Background. Primary pulmonary lymphoma is a rare disease. The clinical characteristics, methods of treatment, and outcomes are not well elucidated. Methods. A retrospective review of primary pulmonary lymphoma cases at a single institution from 1990 to 2002 was performed. Results. Eighteen patients were included, with a mean follow-up of 2.9 years. Fourteen patients had mucosaassociated lymphoid tissue (MALT) lymphoma, 2 had large cell transformation of sheet cells in MALT lymphoma, and 1 each had Hodgkin s disease and follicular lymphoma. Computed tomography-guided biopsy was diagnostic in only two of eight attempts. Eleven patients had disease confined to the pulmonary parenchyma, and 7 had parenchymal disease as well as mediastinal lymphadenopathy. Treatment methods included observation only (n 1), surgery only (n 6), surgery plus chemotherapy (n 8), surgery plus radiotherapy (n 1), and surgery plus chemotherapy plus radiotherapy (n 2). Kaplan-Meier estimate of median time to disease recurrence or death was 6 years. Only 1 patient died of disease-related causes. Patients who had bilateral disease were more likely to have recurrent disease or death (p 0.03). Conclusions. A wide range of treatments were used for patients with generally MALT lymphoma, resulting in good outcomes, and recurrent disease was well controlled. (Ann Thorac Surg 2005;80: ) 2005 by The Society of Thoracic Surgeons Primary pulmonary lymphomas are uncommon, representing less than 1% of lung cancers [1], fewer than 1% of malignant lymphomas [2], and accounting for only 3.6% of extranodal lymphomas [3]. The incidence of primary pulmonary lymphoma peaks in the sixth and seventh decades of life, and the ratio of male to female patients is close to 1:1 [4]. Immunosuppression is a known risk factor for the development of lymphoma, and non-hodgkin s lymphoma occurs in at least 2% of all patients with acquired immunodeficiency syndrome a 200-fold higher rate than the general population [5]. Lymphoma occurring in the post-transplant setting has a different but related pathophysiology, associated with acute Epstein-Barr virus infection in the immunosuppressed host [6]. A revised European-American lymphoma (REAL) classification system for lymphoma histology was published in 1994, and is used extensively for all types of lymphoma [7]. The Ann Arbor staging system has been widely used for lymphomas of all types, and is summarized in Table 1 [8].A commonly used set of criteria for primary pulmonary lymphoma proposed by L Hoste and associates [9] is lymphoma with (1) involvement of the lung, lobar, or primary bronchus, with or without mediastinal involvement, and (2) no evidence of extrathoracic lymphoma at the time of diagnosis or for 3 months thereafter. To contribute to the literature available on this subject, a retrospective chart review of patients diagnosed with primary pulmonary lymphoma at the Massachusetts General Hospital was undertaken. Accepted for publication April 5, Address reprint requests to Dr Graham, University of Colorado Health Sciences Center, Campus Box B-177, Denver, CO 80262; brian.graham@uchsc.edu. Patients and Methods The pathology database at the Massachusetts General Hospital was searched for the period of January 1990 to June 2002 using the keywords pulmonary and lymphoma. Eighty patients were initially identified. Patients were excluded if they failed to meet the criteria proposed by L Hoste and colleagues [9] mentioned above, or had lymphoma in the post-transplant setting. The selection criteria resulted in a list of 18 patients, including 1 who had an initial operation in The patient charts were reviewed for presenting signs, symptoms, and radiologic findings, as well as any previous attempted diagnostic procedures. The details of surgery and the latest notes from follow-up were also obtained. The pathology specimens were reviewed (E.J.M.) to confirm the diagnosis of lymphoma, based on cellular atypia, demonstration of monoclonality, restriction of kappa or lambda light chain for B-cell lymphomas, distortion of lymph node architecture, and other standard criteria used in the diagnosis of malignant lymphoma. Several patients (in addition to the 18 reported in this series) who were previously diagnosed with lymphoma were identified on review to have only benign disease. It was recognized that the REAL classification system [7] is fairly sophisticated, and for surgical staging and prognostication can be more detailed than necessary. Consequently, the disease was identified as one of three categories: mucosa-associated lymphoid tissue (MALT) lymphoma, large cell transformation of sheet cells in MALT (a higher grade of MALT lymphoma), or another large cell lymphoma not arising in or associated with MALT, which was then specifically characterized. Examples of photomicrographs of tissue taken from patients in this series are shown in Figures 1 through 4. Pathologic staging was generally unavailable, as many 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg GRAHAM ET AL 2005;80: PRIMARY PULMONARY LYMPHOMA Table 1. Ann Arbor Pulmonary Lymphoma Staging System [8] Stage I I-E II II-E III III-E IV Description Involvement of one lymph node group only Involvement of lung parenchyma only (can be bilateral) Involvement of two or more lymph node groups above the diaphragm Involvement of lung parenchyma and lymph nodes above the diaphragm Involvement of lymph node groups on both sides of the diaphragm Involvement of lung parenchyma and lymph nodes below the diaphragm Diffuse involvement of one or more extralymphatic organs or tissues 1249 GENERAL THORACIC patients had incomplete resections without lymph node sampling. Consequently, radiographic staging was performed using the system in Table 1, and defining lymph node involvement as any lymph node with a dimension 1.0 cm or larger. Statistical correlations were tested using Stata 6.0 (StataCorp LP, College Station, TX). Fisher s exact test was used to compare categorical data, and Student s t test was used for continuous data; all tests were doublesided, and a p of 0.05 or less was used as the cutoff for significance. An exemption from informed consent, as this study is a retrospective chart review, was obtained from the Partners Health Care Human Research Committee (the overseeing institutional review board) on February 28, Results The group of 18 patients included 6 men and 12 women, with a mean age of 66.4 years (median, 66 Fig 2. Low-grade lymphoma (hematoxylin and eosin, original magnification, 400). The lymphoma has small dark nuclei. years; range, 36 to 83 years). The mean follow-up was 2.9 years (range, 5 weeks to 13 years). The initial presenting symptoms are listed in Table 2. Four of the patients had no symptoms of lymphoma on initial examination, even in retrospect. Three of these patients had their disease initially discovered on a radiographic study for an unrelated indication. In the fourth asymptomatic patient, lymphoma was an incidental finding on a pathology specimen resected for adenocarcinoma (which was itself incidentally discovered on a chest roentgenogram for another indication). All patients had a chest computed tomography (CT) as part of the preoperative workup. The patient with the incidental finding of pulmonary lymphoma on a pathology specimen did have minor nonspecific findings on chest CT corresponding to the location of the lymphoma. The findings on chest CT from all patients are summarized in Table 3. Fig 1. Low-grade pulmonary lymphoma (hematoxylin and eosin, original magnification, 40). Nodules of lymphoma are arrayed in part along lymphatic pathways. Fig 3. High-grade lymphoma forming a solid nodule (hematoxylin and eosin, original magnification, 40). A nodule of lymphoma beneath the pleura has fibrosis and a discrete edge.

3 GENERAL THORACIC 1250 GRAHAM ET AL Ann Thorac Surg PRIMARY PULMONARY LYMPHOMA 2005;80: Fig 4. High-grade lymphoma with large atypical lymphoid cells (hematoxylin and eosin, original magnification, 100). The lymphoma has large vesicular nuclei of varying shape and prominent nucleoli. Table 3. Radiographic Findings on Chest Computed Tomography (n 18 Patients) Radiographic Finding n (% of Patients) Number of opacities 1 10 (56) 2 4 (22) 2 4 (22) Mass ( 3 cm) 6 (33) Nodule(s) only ( 3 cm) 7 (39) Infiltrate a 3 (17) Consolidation a 4 (22) Bilateral disease 7 (39) Lymph node enlargement (at least 1.0 cm) Mediastinal only 5 (28) Hilar and mediastinal 2 (11) Pleural effusion 4 (22) a The distinction between infiltrate and consolidation is by radiologic criteria. Infiltrates are generally inhomogeneous, patchy, and without distinct borders, whereas consolidations are homogeneous, dense, and distinct. After the chest CT identified a pulmonary lesion, 8 patients had an attempted CT-guided biopsy, of which only 2 (25%) were diagnostic. One patient with a successful biopsy had no further operation, whereas the other had a definitive video-assisted thoracic surgery wedge resection of all known lymphoma. The other 16 patients had diagnostic thoracic operations, which were not planned preoperatively as definitive therapeutic procedures. The primary type of operation for all patients is listed in Table 4. The resulting surgical pathologic examination showed that most patients (n 14; 78%) had MALT lymphoma. An additional 2 patients had large cell transformation of sheet cells in MALT lymphoma, and 1 each had follicular lymphoma and Hodgkin s lymphoma. The patient with Hodgkin s disease is included in this series because preoperative chest CT showed a 5- by 6-cm left upper lobe mass extending into the hilum, with adjacent hilar lymphadenopathy, and it was unclear whether the tumor originated in the lung or mediastinum. The surgical margins were clean with all known disease Table 2. Symptoms on Presentation (n 18 Patients) Symptom n (% of Patients) Pulmonary Cough 9 (50) Dyspnea 7 (39) Chest pain 3 (17) Wheezing 2 (11) Hemoptysis 1 (6) Systemic Fatigue 2 (11) Weight loss 1 (6) Back pain 1 (6) Arm pain 1 (6) Asymptomatic 4 (22) resected in 4 patients; 1 patient had microscopically positive margins, and 11 had gross disease left behind (often in the contralateral chest). One patient s margins are unclear from reviewing the pathologic specimen and operative records. Postoperative workup included staging the disease. As part of this workup, most patients had CT scans of their abdomen and pelvis, and other commonly performed studies included positron emission tomography and gallium scans. In the patients reported in this series, all patients had negative extrathoracic imaging by definition, as they would not meet the criteria for primary pulmonary lymphoma otherwise. On the basis of the chest CT, 11 (61%) of the patients had disease confined to the lung parenchyma (radiographic stage I-E), whereas the other 7 (39%) patients had pulmonary disease and mediastinal lymphadenopathy (radiographic stage II-E). An additional staging study was bone marrow biopsy, performed in 9 patients, which was positive in 1. It was decided to include this patient in the series, although violating the precise requirements for primary pulmonary lymphoma, as marrow involvement was the only manifestation of extrathoracic disease and was diagnosed after the pulmonary disease. After the operation, the majority of patients received adjuvant therapy, as shown in Table 5. No patients received neoadjuvant therapy, as the diagnosis was almost always Table 4. Principal Operation (n 18 Patients) Operation VATS wedge resection 9 Open lobectomy 3 Open wedge resection 3 Mediastinoscopy / Chamberlain 2 CT-guided biopsy only 1 CT computed tomography; surgery. VATS video-assisted thoracoscopic n

4 Ann Thorac Surg GRAHAM ET AL 2005;80: PRIMARY PULMONARY LYMPHOMA Table 5. Adjuvant Therapy (n 18 Patients) Adjuvant Therapy n (%) Chemotherapy 8 (44) Radiotherapy 1 (6) Chemotherapy and radiotherapy 2 (11) No adjuvant therapy 7 (39) 1251 GENERAL THORACIC unknown before the operation. Three patients had chemotherapy only after disease recurrence, and the remainder of patients who received adjuvant therapy had it in the immediate postoperative period. Two patients received combined chemotherapy and radiotherapy: the patient with Hodgkin s disease, and another patient with MALT lymphoma who had respiratory failure in the setting of a postobstructive pneumonia. Two of the patients who received chemotherapy initially required additional chemotherapy later for recurrent disease. The patient who only had a CT-guided biopsy received no subsequent therapy, and had disease stable at follow-up 6 years later by chest CT. Chemotherapy regimens included steroids alone, rituximab, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisolone), and ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine), as well as combinations of rituximab with other regimens. The long-term outcomes in this series of patients are in listed Table 6, and Kaplan-Meier curves showing overall survival and disease-free survival are in Figures 5 and 6, respectively. One patient was known to have died of disease-related causes; she had a history of congestive heart failure and recent myocardial infarction, and died 1 month after her operation as a result of postoperative sepsis. Potential risk factors for developing the disease were evaluated. Eleven patients were smokers and 6 were nonsmokers (1 patient s smoking status is unknown). Two patients had probable autoimmune diseases: one had type 1 diabetes mellitus, and the other had alopecia totalis. Lactate dehydrogenase levels were measured in 8 patients, and had a mean value of 293 U/L (range, 161 to 534 U/L; normal range, 0 to 210 U/L). An attempt was made to find prognostic indicators that correlated with survival, and the results are shown in Table 7. Higher stage disease, by the Ann Arbor staging system, was associated with statistically not significantly worse outcomes. As might be expected, patients who received adjuvant therapy did worse, likely because their disease required the use of adjuvant therapy, and a Fig 5. Kaplan-Meier curve of overall survival. (MALT mucosaassociated lymphoid tissue; Pts patients.) Table 6. Long-Term Outcome (n 18 Patients) Outcome n (%) Recovered from disease 10 (56) Persistent poor quality of life because of disease 4 (22) Died of disease 1 (6) Died of other causes 2 (11) Died of unknown cause 1 (6) Fig 6. Kaplan-Meier curve of disease-free survival. (MALT mucosa-associated lymphoid tissue; Pts patients.)

5 GENERAL THORACIC 1252 GRAHAM ET AL Ann Thorac Surg PRIMARY PULMONARY LYMPHOMA 2005;80: Table 7. Prognostic Indicators: Factors Increasing the Probability of Disease Recurrence or Death (n 18 Patients) Factor Risk Ratio p Value Received any adjuvant therapy Infinite Bilateral disease Received adjuvant therapy postoperatively Pathology showing high-grade transformation Not microscopically clean surgical margins Stage II-E disease LDH 1.5 upper limit of normal ( 315 U/L) LDH lactate dehydrogenase. subgroup analysis of just those patients who received adjuvant therapy shortly after their operation did not find any detrimental correlation. There was also no correlation between age and disease-free survival (p 0.66). Comment This small series looks at the presentation, treatment, and outcome of 18 patients with primary pulmonary lymphoma, of whom the majority had MALT lymphoma. An additional 2 patients had large cell transformation of sheet cells in MALT lymphoma, which is a higher grade of MALT lymphoma. These lymphomas are, as the abbreviation signifies, lymphomas arising in mucosa-associated lymphoid tissue. Mucosa-associated lymphoid tissue is a general term that includes BALT (bronchus-associated lymphoid tissue) and GALT (gastrointestinal lymphoid tissue). All MALT lymphomas are B-cell lymphomas, often with plasmacytoid differentiation, and most are low grade, but transition to a higher grade occurs in a minority of cases. Mucosa-associated lymphoid tissue lymphoma is generally considered to have a good prognosis at the time of diagnosis, with one study reporting greater than 80% survival at 5 years in 22 patients [10]. The behavior and natural history of MALT lymphoma is similar for disease in different organ systems [10]. The most common location of MALT lymphoma is in the gastric mucosa (associated with Helicobacter pylori infection). The cause of MALT lymphoma is not completely determined, but is frequently associated with chronic inflammation. For example, the pathogenesis of H. pylori infection leading to gastric MALT lymphoma proceeds along the sequence of infection, lymphocyte recruitment, lymphocyte proliferation, genetic transformation, and malignancy [11]. It has been proposed that a chronic inflammatory origin such as infection, smoking, or autoimmune disease may play a role in the development of pulmonary MALT lymphoma [12]. Of the 16 patients in this series with MALT lymphoma, 9 were smokers, although both patients with high-grade disease were nonsmokers. Two patients had histories of probable autoimmune diseases, and none had a previously diagnosed chronic pulmonary disease or human immunodeficiency virus infection. The incidence of pulmonary MALT lymphoma may be increasing, and is most likely associated with more aggressive evaluation and treatment of all types of lung cancer. Previously when a patient was diagnosed with a large lung mass or bilateral disease, aggressive therapy was not indicated. A small subset of these patients would have very slowly progressive disease, and such miracle cases would live far beyond the expected median survival. In actuality, these patients may have had a lung cancer such as lymphoma, which grows very slowly and is either benign or mildly malignant. As the treatment for all types of lung cancer has improved, physicians are more likely to precisely evaluate all lung lesions and identify the rare lymphomas. Bilateral disease is more suggestive of pulmonary lymphoma, as the differential diagnosis is narrowed to lymphoma, nonmalignant pulmonary disease, metastatic cancer, metachronous primary cancers, or a unilateral process affecting both sides such as bronchoalveolar carcinoma [13]. Another cause of the increased incidence of pulmonary lymphoma may be an increased use of imaging studies (such as whole-body CT scans) in asymptomatic patients. These studies can pick up lung lesions that are benign or mildly malignant, and would have otherwise remained asymptomatic. Three of the patients in this series had their otherwise asymptomatic lymphomas found on imaging studies for unrelated indications. The diagnosis of primary pulmonary lymphoma may be made by any one of a number of different procedures. In this series, CT-guided biopsy of the pulmonary lesion was only successful 25% of the time. Other studies have reported utility with bronchoalveolar lavage [14], but bronchoalveolar lavage alone does not allow the morphologic analysis necessary to make a specific diagnosis. Diagnostic operative procedures range from lymph node biopsy to wedge biopsy or lobectomy. After MALT lymphoma has been diagnosed, appropriate staging should be performed to rule-out extrathoracic disease. The first step is a CT scan of the chest, abdomen, and pelvis to look for lymphadenopathy, masses, or splenic enlargement. Radiotracer imaging with positron emission tomography or gallium is generally less helpful, as there may be little radiotracer uptake in low-grade disease [15]. Extranodal lymphoma also may involve the bone marrow [11, 16], so a bone marrow biopsy is often indicated. In this series, bone marrow biopsy was performed in 9 patients, and was positive in 1 patient with large cell transformation in MALT lymphoma (who otherwise had stage I-E disease). Other useful tests for staging are lactate dehydrogenase and 2 -microglobulin levels to indicate the burden of disease [10], although in this series lactate dehydrogenase was not a useful prognostic indicator for the 8 patients who were tested. After staging the patient, the next step is deciding whether adjuvant therapy is indicated. Frequently the diagnostic biopsy (by wedge resection or lobectomy) resects the entire lesion. If the pathologic diagnosis is MALT lymphoma without evidence of higher-grade transforma-

6 Ann Thorac Surg GRAHAM ET AL 2005;80: PRIMARY PULMONARY LYMPHOMA tion and staging finds no disease elsewhere, a complete resection may be considered definitive, and no further therapy is required. If there is residual disease, disease in the contralateral chest, or extrathoracic disease, either chemotherapy or radiotherapy (if the lesion is localized) may be considered. In this series, bilateral disease (independent of pathologic diagnosis) was associated with a higher risk of disease recurrence or death, warranting more aggressive therapy. Mild chemotherapy regimens include rituximab, chlorambucil, and CVP (cyclophosphamide, vincristine, and prednisolone). A patient with recurrent disease may be considered for more aggressive chemotherapy regimens, including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine). Rituximab may be added to any of the other regimens. The specific example of a patient who has the diagnosis of localized MALT lymphoma made by CT-guided biopsy may choose to have any one or a combination of definitive resection, chemotherapy, or radiotherapy, all of which seem to be equally effective at preventing recurrence [17]. An alternative in an asymptomatic patient with localized low-grade disease diagnosed by CT-guided biopsy is observation only, as performed in 1 patient in this series, reserving treatment for possible future progression of disease based on symptoms or radiographic progression. This patient has remained asymptomatic and her disease stable by annual chest CT. Previous series have mentioned in passing a few patients who received no specific treatment [18], and a published group of 3 patients in Singapore with low-grade small lymphocytic lymphoma were all alive and doing well a mean of 20 months after diagnosis [19]. Even if patients have had definitive surgical treatment, they should be referred to a medical oncologist both to ensure that the staging is adequate with no disease elsewhere, and to follow the patient for a long time, as this indolent disease may recur after many years [17, 20]. Follow-up studies looking for recurrence may include chest roentgenogram or chest CT. The prognosis for patients with primary pulmonary lymphoma is generally quite good. One large series of 70 patients reported a 94% survival at 5 years for low-grade primary pulmonary lymphoma, and a median survival of 3 years for high-grade disease [18]. Another series with 48 patients reported a 68% 5-year survival for primary pulmonary MALT lymphoma and a 65% 5-year survival for non-malt lymphoma [21]. In this series, the Kaplan-Meier estimate of median time to disease recurrence or death was 6 years. Furthermore, no patients died after disease recurrence, as all patients with disease recurrence were treated and their disease suppressed with chemotherapy. Overall, primary pulmonary lymphoma is a rare lung cancer, but the prognosis is good. Many patients are asymptomatic at the time of diagnosis. Treatment options for localized disease include observation, definitive resection, chemotherapy, or radiotherapy. Surgical cure is not possible if there is diffuse or multifocal disease, but patients still have a favorable prognosis, particularly if large cell transformation has not occurred. The median time to disease recurrence or death in this series is 6 years, comparable with previously published studies, and patients who did have disease recurrence were all treated successfully with chemotherapy. Patients can have poor outcomes in the unusual circumstance when the disease presents in a fulminant manner with extensive extrathoracic disease, or if there is significant comorbidity. 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