Malignant primary lymphoproliferative tumors of the lung are rare and represent a small percentage of all primary malignant neoplasms of the lower respiratory tract. Much of the current knowledge regarding these tumors has been generated relatively recently—over the past 25 years or so—as a consequence of the widespread use of immunohistochemical studies and increased awareness of the occurrence of these neoplasms. By contrast, in the early 1980s, fewer than 200 cases had been reported, and in the previous 10 to 12 years, just over 100 cases were published.
Subsequent to new developments and classification schemes, characterizations of such tumors as “pulmonary pseudolymphoma,” “bronchus-associated lymphoid tissue (BALT)-type lymphoma,” and “BALToma” have fallen out of favor as diagnostic entities. Bienenstock and coworkers introduced the latter two terms in 1973, describing the morphologic and functional characteristics of bronchial lymphoid tissue. The designation lymphoid interstitial pneumonitis (LIP) is now confined to inflammatory lesions of the lung. Previously, it was thought that either pseudolymphoma or LIP represented a premalignant condition, because both have been reported to develop changes consistent with malignant transformation ; a more stratified histologic approach, however, has been advocated by some investigators. Currently, the preferred designation is marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type .
The criteria for diagnosing primary pulmonary lymphoma have also changed over the years. Initially, it was defined as a unilateral process, with or without hilar involvement, and with no mediastinal disease. This definition, however, was recognized to eliminate cases with bilateral involvement. Some investigators have found that the assessment between primary and secondary tumors is difficult to make on histologic grounds, because both processes may share similar histopathologic features. Therefore, “primary malignant lymphoma of the lung” represents an elusive diagnosis for the pathologist, who may not have access to the entire clinical history, which would tell whether the patient has enlarged lymph nodes elsewhere or tumor nodules in an extrathoracic location. Consequently, in this setting, assessment requires careful clinical and radiologic correlation.
For the practical assessment of lymphomas in the lung, the recognized clinical entities can be separated into two main families:
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Non-Hodgkin’s lymphomas
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Marginal zone B cell lymphoma, MALT type
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Diffuse large cell B cell lymphoma
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Anaplastic large cell lymphoma
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Lyphomatoid granulomatosis
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Hodgkin’s lymphoma
MARGINAL ZONE B CELL LYMPHOMA, MUCOSA-ASSOCIATED LYMPHOID TISSUE TYPE
Marginal zone B cell lymphoma of the MALT type may be the most common type of pulmonary lymphoma, accounting for more than 60% of all pulmonary lymphomas. Because the current terminology used to identify this tumor is new, frequency must be extrapolated from data available in previously published series.
In 1983, Koss and colleagues presented a study of 161 patients with what the investigators called primary non-Hodgkin’s lymphoma of the lung or, in a minority of the cases, pseudolymphoma of the lung. Although the tumors were classified according to the current schema of the time, it is likely that more than 70% of the non-Hodgkin’s lymphoma cases may have represented MALT-type lymphomas, and probably less than 10% represented diffuse large cell lymphoma. As noted, also included in this study were so-called pseudolymphomas, accounting for 14% of the cases. Most of the patients in this study were in the sixth or seventh decade of life and were asymptomatic, with a solitary nodule or infiltrate in the lung found incidentally on a chest radiograph. Clinical signs and symptoms, when present, included cough, dyspnea, hemoptysis, and upper respiratory infection. More constitutional manifestations such as weight loss were documented in a minority of patients. Some patients had a history of Sjögren’s syndrome or systemic lupus erythematosus. On radiologic examination, a pulmonary nodule of variable size (ranging from 2 to 8 cm) was the most common finding. Hilar adenopathy was present in a minority of cases.
In 1984, Herbert and associates described nine cases of primary malignant lymphoma of the lung and suggested that these lymphomas arise from bronchus-associated lymphoid tissue, which would explain the histopathologic features as well as the clinical course (the tumor is confined to the lung for long periods of time). The patients in this study were between the ages of 30 and 68 years and presented with ill-defined consolidated areas in the lung that ranged from 2 to 8 cm in greatest dimension. Clonality was demonstrated by immunohistochemical analysis in four cases, suggesting that if these lymphomas of the lung were to disseminate, they might spread widely to other mucosal sites. Development of gastric lymphomas of the MALT type was documented in two of the cases.
L’Hoste and coworkers reported a series of 36 primary lymphomas of the lung in which patient age ranged from 12 to 75 years; however, only one patient was younger than 30 years. These patients presented with unilateral or bilateral disease. At least 21 of the lymphomas were low-grade tumors and probably were of the MALT type. These workers were not able to discriminate on histopathologic grounds between tumors that recurred and eventually disseminated and those that followed a more indolent course.
Addis and colleagues documented 15 primary pulmonary lymphomas, some of which had features that previously had been associated with the so-called pulmonary pseudolymphoma. These investigators suggested that pulmonary lymphomas arise from the centrocyte-like cells normally present in the bronchus-associated lymphoid tissue and warned that some of the cases previously identified as pseudolymphomas or LIP may in fact represent examples of pulmonary lymphoma. Similar findings also have been documented by different investigators. An unusual case of MALT-type lymphoma has been reported in an HIV-positive 7-year-old child. Tamura and associates studied 12 cases of pulmonary B cell lymphoma for the presence of Epstein-Barr virus (EBV) infection and found that none of the cases showed signaling for the receptor EBER-1 using the antisense probe, suggesting that primary pulmonary MALT-type lymphoma is not associated with an EBV infection. In other unusual presentations, simultaneous involvement of the conjunctiva has been reported, and the disorder also may manifest as chronic pneumonia.
More recently, two studies have focused on the association of MALT-type pulmonary lymphoma with Sjögren’s syndrome and other autoimmune disorders. Sophisticated radiologic techniques have demonstrated that MALT-type lymphomas may manifest as a single nodule or in a consolidated pattern with multiple nodular areas of consolidation, bronchiectasis, or bronchiolitis, whereas on positron emission tomography (PET) scans, the lesions show heterogeneous (more common) or homogeneous fluorodeoxyglucose (FDG) uptake. More recent series have confirmed previous clinical and histopathologic features of these tumors.
Macroscopic Features
The tumors may be unilateral or bilateral and may present either as a distinct solitary pulmonary mass, localized pulmonary infiltrate, or diffuse pulmonary infiltrate. When these lesions manifest as a solitary mass, tumor size may range from 1 cm to more than 5 cm in greatest dimension. In some series, tumors larger than 10 cm have been recorded. They are whitish, without areas of necrosis or hemorrhage, and in some cases central scarring has been identified.
Histopathologic Features
The low-power view displays an atypical homogeneous lymphoid proliferation with cellular elements arranged in different growth patterns. A well-demarcated tumor nodule or mass that replaces and obliterates the normal lung parenchyma may be visible ( Fig. 10-1 ), or the neoplastic cellular proliferation appears as multiple small, ill-defined nodules scattered in the lung parenchyma. Less commonly, the tumor may manifest as an ill-defined infiltrate tracking vascular structures. The tumor may be observed invading the pleura, or involving the bronchial cartilage ( Fig. 10-2 ). The presence of tumor in the visceral pleura has been recognized as an unequivocal feature of malignancy in a lymphoid proliferation. Higher magnification shows lymphoid infiltrate invading epithelial structures such as the bronchial epithelium, and forming the so-called lymphoepithelial lesion characteristically seen in MALT-type lymphomas ( Fig. 10-3 ). The neoplastic cellular proliferation is composed of small lymphocytes with mild nuclear irregularities admixed with scattered immunoblasts. The lymphoid proliferation may display a clear halo surrounding the nucleus of the lymphoid cells, in a manner reminiscent of parafollicular B cells; while in other areas the lymphoid proliferation may appear plasmacytoid ( Figs. 10-4 to 10-8 ). The presence of Dutcher bodies appears to correlate more often with malignant processes, rather than reactive ones.
Other features that may be present in differing proportions in MALT-type lymphomas are sarcoid-like granulomas, multinucleated giant cells, and cholesterol cleft granulomas. These unusual features may be seen in up to 50% of MALT-type lymphomas. Germinal centers also may be seen in these cases ( Fig. 10-9 ); this feature was once considered a characteristic of the so-called pseudolymphoma. Lymph node involvement, another feature once considered an important indication of malignancy in lymphoid proliferations, may be present in less than one third of MALT-type lymphomas.
Malignant cells admixed with reactive follicles and polytypic plasma cells also may be observed.
Immunohistochemistry
Because lymphoid proliferations may appear in the lung owing to a variety of conditions, immunohistochemical studies are vital to an accurate diagnosis. Flow cytometry and gene rearrangements may provide more insight into the true nature of the infiltrate in many difficult cases. Researchers have highlighted several different immunohistochemical features for these tumors, and as new antibodies are developed and their specificity and sensitivity are improved, the accepted immunohistochemical features continue to change. In a study of 45 cases of pulmonary lymphoma, Nicholson and coworkers noted that all of the tumors studied by immunohistochemistry showed positive staining for CD20 (a B cell marker) with a variable number of reactive CD3 (a T cell marker)-positive cells. The investigators also found that CD21 can be used to document the presence of germinal centers, even when this morphologic feature was not apparent. In a study of 26 lymphoid lesions, Bégueret and colleagues found that these tumors will express CD20 and CD43. MALT-type lymphomas usually express heavy chain for IgM or IgA and, less frequently, for IgG. Immunohistochemical studies also should be performed to document monoclonality; the use of κ and λ light chains may aid in the diagnosis, and polymerase chain reaction (PCR) analysis or gene rearrangement studies also should be considered. In general, MALT-type lymphomas demonstrate negative staining for CD23, CD5, Bcl-1, and Bcl-2.
Translocations have been reported in MALT-type lymphomas. The most common is t(11;18)(q21;q21), which can occur in 50% of these cases. Other translocations, including t(14;18)(q32;q21) and t(I;14)(p22;q32), have been recorded. More recently, a case with Bcl-10 expression and novel translocation t(1;2)(p22;p12) immunoglobulin κ chain–Bcl-10 has been documented.
Differential Diagnosis
The most important considerations in the differential diagnosis are nodular ( Figs. 10-10 and 10-11 ) and diffuse hyperplasia of the bronchial lymphoid tissue ( Figs. 10-12 to 10-14 ) and secondary involvement of the lung by malignant lymphoma. In the past, the presence of germinal centers was used as a factor distinguishing between reactive and neoplastic lymphoid proliferations. Neoplastic lymphoid proliferation also may show the presence of germinal centers, however; thus, it is not a completely reliable feature of reactive lesions. These conditions share some clinical and radiologic features as well. In a study of 18 patients with LIP (diffuse hyperplasia of the bronchial lymphoid tissue), Koss and associates found that the median age at diagnosis was 56 years, with clinical signs and symptoms of cough, dyspnea, or chest pain. Findings on the initial radiologic examination included patchy interstitial infiltrates or poorly defined pulmonary nodules. On histologic examination, the lesions displayed interstitial infiltrates composed of lymphocytes and plasma cells, with 47% of the cases showing germinal centers and 72% showing interstitial giant cells (see Figs. 10-10 to 10-12 ). In the cases studied by immunohistochemistry techniques, the investigators documented the presence of a polytypic infiltrate. In one case, the patient died of disseminated lymphoma, which raises the possibility that such lesions may develop into full-blown lymphomas. In this setting, mono- or polyclonality must be documented to properly classify the process as reactive or neoplastic.
Determining whether the tumor is a primary or a secondary lung neoplasm may be difficult on histopathologic grounds alone. Costa and colleagues published a study of 21,157 autopsies in which 414 of the cases represented systemic lymphoma, 85 showed lung involvement, and 43 represented B cell lymphomas. Five patterns of infiltration were documented: perivascular-peribronchial, nodular, alveolar, interstitial, and pleural. These patterns of involvement have been seen in primary pulmonary lymphomas, making the distinction very difficult on histologic grounds alone.
Prognosis and Treatment
The prognosis for patients with MALT-type pulmonary lymphoma is relatively good. Vallisa and associates documented survival rates of 100% at 2 years and 93% at 5 years; they recommend that in cases of stable low-grade lymphoma, observation alone constitutes an appropriate management approach, whereas in cases that demonstrate progression of disease, the use of chemotherapy is indicated. Ferraro and coworkers documented survival rates of 91%, 68%, and 53% for 1, 5, and 10 years, respectively. In this series, 19 of the patients (40%) underwent complete surgical resection.
Other researchers have questioned whether MALT-type lymphomas should be treated immediately. In a study by Koss and associates, only 12 of 101 patients with lymphoma died in a period of 5 years, and only 18 died in a period of 15 years. In Herbert and coworkers’ series, only one of nine patients died within a follow-up period of 15 years. Survival rates of 88% at 5 years have been recorded by other investigators. In a study of 11 patients, Troch and colleagues suggested that MALT-type lymphoma of the lung is an indolent process with the potential for spontaneous regression. Accordingly, these workers suggested a watch-and-wait policy in stable cases. Other researchers have stated that when the tumor manifests as a single pulmonary mass, complete surgical resection may constitute optimal management.
DIFFUSE LARGE B CELL LYMPHOMA
In general, primary diffuse large B cell lymphomas of the lung are rare, accounting for no more than 10% to 15% of pulmonary lymphomas. It is likely that diffuse large B cell lymphomas represent less than 1% of all pulmonary neoplasms.
The clinical and radiologic features are similar to those of MALT-type pulmonary lymphoma. No gender predilection has been documented, and most patients are in their sixth decade of life. Patients may present with pulmonary symptomatology or with more systemic symptoms. A single mass or multiple unilateral or bilateral pulmonary nodules may be seen on radiographic studies, with or without lymph node involvement.
In 1982, Colby and Carrington described 20 cases of pulmonary lymphoma, 10 of which represented primary tumors in the lung and 10 representing secondary pulmonary involvement. Although the description emphasized that primary and secondary pulmonary malignant lymphomas show similar histopathologic features, these cases probably were of the diffuse large B cell type. The investigators also stressed the presence of vascular lesions commonly associated with lymphomatoid granulomatosis. In Koss and coworkers’ series of 161 cases, it is possible that less than 10% of the cases described represented diffuse large B cell type lymphoma.
In a series of 45 cases of non-Hodgkin’s lymphoma of the lung, Nicholson and associates identified 6 cases associated with autoimmune disease. Three of these patients had cryptogenic fibrosing alveolitis treated with long-term immunosuppressive therapy. Five of the six cases corresponded to diffuse large B cell lymphoma and one to a low-grade lymphoma. The investigators suggested an association between autoimmune disease and lymphomas. Other workers also have reported the association of diffuse large B cell lymphoma and cryptogenic fibrosing alveolitis. In Ferraro and coworkers’ account of 48 patients with primary non-Hodgkin’s lymphoma of the lung, 13 cases may have been of the diffuse large B cell type, although the emphasis in this series was on the low-grade MALT-type lymphoma.
Macroscopic Features
Diffuse large B cell lymphomas may manifest as a solitary pulmonary mass or as unilateral or bilateral pulmonary nodules. Tumor size may range from 1 cm to more than 5 cm in greatest dimension, and necrosis may be present on the cut surface of the tumor, although it is not a consistent feature. The tumors are well circumscribed and light tan in color, with a soft consistency.
Histopathologic Features
The low-power view will show a homogeneous neoplastic cellular proliferation destroying and replacing normal pulmonary parenchyma ( Fig. 10-15 ). The tumor may appear as a well-defined mass or may exhibit diffuse infiltration into the pulmonary interstitium with extension along vascular structures ( Figs. 10-16 and 10-17 ). At higher magnification, a neoplastic cellular proliferation composed of larger cells with round to oval nuclei and prominent nucleoli can be seen ( Fig. 10-18 ). Mitotic figures are commonly encountered, and areas of necrosis also may be present, ranging in extent from focal to more extensive. Invasion of normal pulmonary structures such as the bronchial wall and pleura is common. Some investigators have made special mention of the areas of low-grade MALT-type lymphoma undergoing transition to a high-grade process; thus, some of these tumors will be designated high-grade MALT-type lymphomas, although this term may not be appropriate.
Immunohistochemical Features
Because the neoplastic cellular proliferation may show cellular pleomorphism, it is important to rule out an epithelial tumor. Therefore, the use of epithelial markers, including keratins and epithelial membrane antigen (EMA), should be considered. A panel of immunohistochemical studies using B cell and T cell markers also should aid in the proper classification of these tumors. Neoplastic cells will show positive staining for B cell markers, CD20 (L-26) in particular, and negative staining for T cell markers. In some cases, some T-reactive cells may show positive staining using T cell markers. Other immunohistochemical studies to determine clonality or the use of molecular techniques should help in the final diagnosis.
Differential Diagnosis
Epithelial neoplasm, especially carcinoma, is an important consideration in the differential diagnosis. Some undifferentiated or pleomorphic carcinomas may mimic a lymphoid neoplasm. Therefore, use of a broader panel of immunohistochemical studies, including those utilizing keratins and EMA, should help in obtaining an accurate diagnosis. Other types of lymphomas also should be considered; however, use of additional immunohistochemical markers for B and T cells and other molecular techniques, including gene rearrangement studies, may permit more specific classification of these tumors.
Prognosis and Treatment
As indicated by data from some of the cases published in the literature, diffuse large B cell lymphomas may not share the favorable prognosis for MALT-type lymphomas. In the study reported by Colby and Carrington, the outcome was poor, with one half of the patients dead by 24 months. In Nicholson and coworkers’ study of six patients with this neoplasm, three patients were evaluated at autopsy. Two of the three remaining patients died at 2 weeks and 6 months later, respectively, and only one patient survived 4 years. These patients also had an associated autoimmune condition that may have had an effect on overall survival. However, in the 13 cases described by Ferraro and colleagues as non–MALT-type lymphoma, the survival rates at 1, 5, and 10 years were 85%, 65%, and 53%, respectively. Some researchers have suggested that rituximab may improve the response to the CHOP regimen (cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone) commonly used in the treatment of diffuse large B cell lymphomas.
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