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Ann Thorac Surg 2000;69:993-997
© 2000 The Society of Thoracic Surgeons

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ORIGINAL ARTICLES: GENERAL THORACIC

Primary non-Hodgkin’s lymphoma of the lung

^a Division of Thoracic Surgery, Department of Surgery, Mayo Clinic and Foundation, Rochester, Minnesota, USA
^b Department of Pathology, Mayo Clinic and Foundation, Rochester, Minnesota, USA

Address reprint requests to Dr Trastek, Division of General Thoracic Surgery, Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN 55905
e-mail: trastek.victor{at}mayo.edu

Presented at the Poster Session of the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Primary non-Hodgkin’s lymphoma of the lung is a rare entity. Although the prognosis is favorable, clinical features, prognostic factors, and patient management have not been clearly defined.

Methods. We reviewed retrospectively the records of 48 patients operated on for primary pulmonary non-Hodgkin’s lymphoma. The study group consisted of 21 male (44%) and 27 female (56%) patients with a mean age of 61.8 years. Thirty-seven and a half percent of patients were asymptomatic, and 62.5% were seen with pulmonary symptoms, systemic symptoms, or both. A definitive diagnosis was obtained by thoracotomy in 90% of patients, thoracoscopy in 8%, and anterior mediastinotomy in 2%.

Results. Complete surgical resection was possible in 19 patients (40%). A mucosa-associated lymphoid tissue lymphoma (MALT) was found in 35 patients and lymphoma that was not of this type, in 13. The 1-year, 5-year, and 10-year survival rates were 91%, 68%, and 53%, respectively in the group with mucosa-associated lymphoid tissue lymphoma and 85%, 65%, and 64% in the group with lymphoma that was not of the mucosa-associated lymphoid tissue type. None of the prognostic factors studied (mode of presentation, smoking history, bilateral disease, postoperative stage, complete resection, adjuvant chemotherapy, histology) significantly influenced patient survival.

Conclusions. Primary non-Hodgkin’s lymphoma of the lung occurs with nonspecific clinical features. Although patient survival is good, prognostic factors could not be identified.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Extranodal lymphomas comprise only 3% to 5% of all lymphomas and are most frequently discovered in the stomach and gastrointestinal tract. Primary pulmonary non-Hodgkin’s lymphoma is a rare entity encompassing only 0.4% of all lymphomas. Secondary involvement of the lung in patients with a history of lymphoma is much more frequent, however, with an incidence of 25% to 40%.

Most primary lymphomas of the lung arise from the mucosa-associated lymphoid tissue (MALT) of the bronchus. The presence of MALT in the lung was first described by Bienenstock and colleagues [1] in 1973. Most authors believe MALT is not a normal constituent of the human bronchial tree but rather is acquired in response to long-term exposure to various antigenic stimuli such as smoking, infection, or autoimmune disease [2]. Similarly, MALT is not normally found in the stomach but is associated with chronic Helicobacter pylori gastritis [3]. Low-grade lymphomas of MALT discovered in the gastrointestinal tract have been reported to regress completely in up to 70% of patients once the H pylori has been eradicated [4, 5].

Although the prognosis associated with primary non-Hodgkin’s lymphoma of the lung is favorable, optimal management has not been clearly defined. The objectives of this review are to study the clinical features of primary non-Hodgkin’s lymphoma of the lung, evaluate the role of surgery, and try to identify possible prognostic factors.

	Material and methods

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From 1975 to 1995, 189 patients with a diagnosis of lymphoma underwent a thoracic procedure at the Mayo Clinic. Forty-eight of these patients were found to have primary non-Hodgkin’s lymphoma of the lung. The following were used to identify them: involvement of the lung with non-Hodgkin’s lymphoma; no past history of lymphoma; no evidence of extrathoracic disease at the time of diagnosis including negative results of abdominal computed tomographic scanning and bone marrow biopsy; and no evidence of extrathoracic disease up to 6 months after the initial diagnosis. The remaining 141 patients were excluded from this review because of secondary involvement of the lung with lymphoma in 119 patients, incomplete evaluation in 9, Hodgkin’s lymphoma in 2, benign disease in 3, and incorrect diagnosis in 8.

The patient records were reviewed, and the following data were collected: smoking and past medical history, symptoms and roentgenographic findings at the time of diagnosis, diagnostic procedure, surgical intervention, postoperative course, histology and stage of the tumor, and long-term survival. Patient follow-up was obtained through office visits or by telephone interview.

The histologic diagnosis of primary non-Hodgkin’s lymphoma of the lung (MALT and non-MALT types) was reviewed in each patient by a group of pathologists. The diagnosis of low-grade lymphoma of MALT was based on the following features: extranodal, small lymphocytic B-cell tumor; cellular heterogeneity including centrocytelike cells, monocytoid B cells, small lymphocytes, and plasma cells; cells arranged in sheets, thick cuffs, and micronodules with a characteristic lymphangitic distribution; presence of distinctive lymphoepithelial lesions (infiltration of the bronchial mucosa and mucous glands by centrocytelike cells); and presence of reactive lymphoid follicles, hyaline sclerosis, vascular and pleural infiltration, and occasional amyloid deposition with granuloma. Non-MALT types of primary lymphoma of the lung include all non-Hodgkin’s lymphomas without the features just listed, as classified histologically by the working formulation [6]. The staging classification used for these extranodal lymphomas is as follows:

Stage I E: Involvement of lung only (can be bilateral)

Stage II 1E: Lung and hilar lymph nodes

Stage II 2E: Lung and mediastinal lymph nodes

Stage II 2EW: Lung and adjacent chest wall or diaphragm

Stage III: Involvement of lung and of lymph nodes below diaphragm

Stage IV: Diffuse involvement of one or more extralymphatic organs or tissues

Patient survival was estimated using the Kaplan-Meier method. Prognostic factors were studied by univariate analysis, and differences in survival were compared using the ² test. A p value of 0.05 or less was considered significant.

Clinical data
The study group consisted of 21 male (44%) and 27 female (56%) patients with a mean age of 61.8 years (range, 15 to 85 years). Nineteen patients (40%) were former or active smokers, 9 (19%) had heart disease, and 3 (6%) had chronic obstructive pulmonary disease. At the time of diagnosis, 18 patients (37.5%) were asymptomatic, and 30 (62.5%) were seen with pulmonary or systemic symptoms or both (Table 1). Cough and dyspnea, occurring in 46% and 23% of patients, respectively, were the most frequent pulmonary symptoms.

To exclude extrathoracic disease, all patients underwent a bone marrow biopsy and a computed tomographic scan of the abdomen. The bone marrow biopsy specimen was normal in all patients, and the computed tomographic scan was within normal limits in 46 patients and showed mild splenomegaly in 2 patients.

Diagnostic and surgical procedures
Definitive diagnosis was obtained with an open thoracotomy in 43 patients (90%), by video-assisted thoracoscopic wedge resection in 4 (8%), and a left anterior mediastinotomy in 1 (2%). At thoracotomy, wedge resection was performed in 21 patients (49%) and incision biopsy in 7 (16%). Formal anatomic resection was performed in the remaining 15 patients and included pneumonectomy in 2, lobectomy in 11, and segmentectomy in 2. Transthoracic needle biopsy and cervical mediastinoscopy were each performed in 7 patients; neither was diagnostic (Table 2).

	Results

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A MALT type of lymphoma (low grade or large cell) was found in 35 patients (73%) and a non-MALT type, in 13 patients (27%) (Table 3). Postoperative staging showed stage I E disease in 37 patients, stage II 2E in 7, stage II 2 EW in 3, and stage III in 1 patient. After operation, chemotherapy was administered to 26 patients (54%), radiation therapy to 2 (4%), and no adjuvant therapy to 20 (42%).

View larger version (9K): [in this window] [in a new window]   Fig 1. Overall survival: actuarial survival (Kaplan-Meier method) of patients with primary lymphoma of the lung after surgical resection.

View larger version (11K): [in this window] [in a new window]   Fig 2. Survival of patients after complete surgical resection with or without postoperative chemotherapy.

View larger version (11K): [in this window] [in a new window]   Fig 3. Survival of patients after incomplete surgical resection with or without postoperative chemotherapy.

	Comment

Top Abstract Introduction Material and methods Results Comment References

The formulation of the MALT lymphoma concept by Isaacson and Wright [9] and the advent of immunohistochemical techniques to detect monoclonality have resolved much of the controversy surrounding the definition of these lymphoid tumors of the lung. Also, a revised classification of lymphoid neoplasms including MALT lymphomas was proposed at a relatively recent consensus conference [10].

Malignant lymphomas arising in MALT remain localized until late in their natural history and thus carry a better prognosis than lymphomas arising in lymph node tissue of similar stage [11, 12]. Prognostic factors influencing survival and optimal therapy for MALT lymphoma, however, have not been clearly defined.

In this review, 37.5% of patients were asymptomatic at the time of diagnosis, a rate similar to that reported by other [11–13]. The presence of constitutional symptoms was not associated with a worse prognosis. Symptoms were generally nonspecific except for a slight preponderance of respiratory abnormalities. The roentgenographic appearance of pulmonary lymphoma is usually described as a alveolar mass or infiltrate with ill-defined margins and air bronchograms [12, 14, 15]. Our findings showing a mass or infiltrate in two thirds of the patients concur with this description. Rounded opacities or nodules, although less common in our study have been reported as a frequent sign in other series [11, 13, 16]. Thus, the roentgenographic appearance is variable and can only suggest the possibility of lymphoma.

Surgical intervention, whether by thoracotomy or VATS, is required for diagnosis in the majority of patients seen with primary pulmonary lymphoma. Bronchoscopy was performed in most patients but had a low diagnostic yield because endoluminal lesions are infrequent. It has been reported that with tumor cell markers and molecular techniques such as flow cytometry, pulmonary lymphoma may be detected by bronchoalveolar lavage [17, 18]. In our experience, neither transthoracic needle biopsy nor mediastinoscopy was useful in obtaining a definitive diagnosis. There are a number of nonneoplastic reactive conditions that can simulate lymphoma, and thus a more generous VATS or open lung biopsy should be performed.

The role of surgery in the management of primary lymphoma of the lung is twofold; to obtain diagnostic tissue and to obtain a therapeutic resection. Tumors that appear to be resectable should be approached with an intent to cure by performing complete surgical resection and a staging lymph node dissection. In patients with a large, nonresectable lesion or with bilateral disease, obtaining sufficient tissue for a diagnosis of lymphoma is the goal. A limited wedge resection or even an incisional biopsy is appropriate in these patients. When a lymphoma is diagnosed on frozen section, a hilar and mediastinal nodal dissection for staging purposes should be carried out. When dealing with an indeterminate, resectable lung mass at thoracotomy, the surgeon’s primary concern is bronchogenic carcinoma. If a complete resection is possible in an otherwise healthy patient, this resection should not be compromised, and obtaining negative margins should be the main objective.

The rate of local recurrences with these tumors has been found to be a high as 50% [11, 13, 19], and thus radical resections including pneumonectomies have been recommended by some authors [20]. Our data, however, do not support the use of extended resections such as pneumonectomies when dealing with primary pulmonary lymphoma. When we compared patient survival, the extent of the resection (complete versus incomplete) did not significantly influence survival. Even the addition of chemotherapy postoperatively did not offer a survival advantage. However, our study is retrospective and includes a relatively small number of patients. Further chemotherapeutic regimens varied greatly over the 20-year study period.

Stage of disease (I E versus II E) was also shown not to be a significant prognostic factor in our series. Presence of regional (hilar) lymph node metastases does not correlate with a worse prognosis [11, 19]. Although our results failed to show a difference in survival, the histologic type of lymphoma should serve as a prognostic factor, as shown by Kennedy and associates [21]. True lymphomas of MALT are low-grade tumors with a slow, indolent course, and long-term survival can be excellent (50% to 70% at 10 years) [11–13, 21]. Non-MALT types of lymphoma of the lung are generally intermediate or high-grade tumors associated with a worse prognosis, as are small lymphocytic tumors of MALT, which show transformation to a large cell type. Patients with localized (stage I E or II E) primary pulmonary lymphoma may be cured with local-regional therapy alone (surgical intervention or irradiation). Combined modality therapy, however, appears to be superior in patients with bulky tumors, residual disease after operation, and an unfavorable non-MALT type of histology [22, 23].

In summary, primary non-Hodgkin’s lymphoma of the lung is a rare entity with generally nonspecific clinical and roentgenographic signs at the time of diagnosis. An open thoracotomy provides a diagnosis in all instances and allows definite therapy for many patients. Specific prognostic factors could not be identified in our review. The histology of the tumor should serve as a prognostic factor and help establish the need of combined modality therapy. Overall, these lymphomas are associated with a good prognosis and excellent long-term survival.

	References

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