Context.—Diagnosis and classification of lymphomas are based on the morphologic, immunologic, and genetic features that the lesional cells share with their normal B and T lymphocyte counterparts. Primary pulmonary lymphomas account for 0.3% of primary lung neoplasms and less than 0.5% of all lymphomas.
Objective.—To describe and summarize the clinical and histopathologic features of the primary pulmonary lymphoma and secondary involvement of the lung by lymphoma.
Data Sources.—Peer-reviewed published literature and personal experience.
Conclusions.—Diagnosis of clonal lymphoid proliferations in the lung has evolved owing to the greater utility of molecular and flow cytometric analysis of tissue. Further studies are needed to best define the clinical and prognostic features, as well as search for targeted therapy for these patients with rare neoplasms.
Primary pulmonary lymphoma is defined as clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no previous extrapulmonary involvement at the time of diagnosis or during the subsequent 3 months. Primary lymphoma of the lung is a rare disorder and represents only 0.3% of all primary pulmonary malignancies, less than 1% of all the cases of non-Hodgkin lymphoma, and 3% to 4% of all the extranodal manifestations of non-Hodgkin lymphoma.1,2 Lymphomatoid proliferation can also involve the lungs either by hematogenous dissemination of non-Hodgkin lymphoma or Hodgkin lymphoma (HL) or by contiguous invasion from a hilar or mediastinal site involved by lymphoma. These conditions are more frequent and are referred to as secondary involvement of the lung by lymphoma. Lymphomas in the lung are usually diagnosed by video-assisted thoracic surgery, open-wedge biopsy, or lobectomy. However, more recently it has been found that bronchial or transbronchial biopsy or computed tomography–guided transthoracic needle biopsy can also yield promising results, if tissue is triaged carefully in clinically suspicious cases.
Diagnosis and classification of lymphomas is based on the morphologic, immunologic, and genetic features that the lesional cells share with their normal B and T lymphocyte counterparts. Special studies such as immunohistochemistry, flow cytometric immunophenotyping, molecular genetics, and cytogenetics have recently evolved that can identify clonal populations in small samples and yield accurate and specific diagnoses. However, lack of clonality does not always prove that the lesion is benign and reactive. In such cases, the morphology and immunoarchitecture of the tissue sections are helpful in making the diagnosis and assessing the lineage of the infiltrate. The clinical features, optimal treatment, and prognostic factors of primary and secondary pulmonary lymphoma are not well defined. The objective of this article is to describe and summarize the clinical and histopathologic features of these neoplasms.
NORMAL LYMPHOID TISSUE IN THE LUNG
The lung contains an extensive lymphatic network that channels lymphatic fluid towards parenchymal, septal, hilar, and mediastinal lymph nodes. Organized lymphoid tissue in the periphery of the normal lung is limited to sparse submucosal aggregates of lymphocytes and intraparenchymal lymph nodes.3 The lymphoid tissue is more substantial centrally along bronchioles and central airways. Various antigenic stimuli, such as smoking, immunologic disease, or chronic infection in the bronchi, initiate the primary and secondary immune response, leading to lymphoid hyperplasia referred to as acquired mucosa-associated lymphoid tissue (MALT). In the lung it is often referred to as bronchus-associated lymphoid tissue. Acquired MALT has a distinctive immune architecture with 4 compartments: B-cell rich follicles, follicular mantle and marginal zones, and T-cell–rich interfollicular regions.
PRIMARY PULMONARY LYMPHOMA
The lung is one of the more common sites where extranodal lymphomas arise, following the gastrointestinal tract, skin, and nervous system.4 Primary pulmonary lymphoma is diagnosed when the lung, bronchus, or both are involved without evidence of mediastinal adenopathy or a mass on the chest imaging and without any diagnosis of extrathoracic lymphoma previously or during the subsequent 3 months. Most cases of primary lymphoma of the lung are of B-cell lineage, and the disease is frequently located in the bronchus-associated lymphoid tissue. These neoplasms are most commonly seen in adults with a median age of about 60 years and rarely develop in children. Most studies show a slight male predominance. Patients often present with pulmonary symptoms such as dyspnea, hemoptysis, chest pain, or constitutional symptoms. However, a majority of low-grade lymphoma patients are asymptomatic. Radiologic findings of primary pulmonary lymphoma are nonspecific, with single or multiple, unilateral or bilateral lesions forming nodules, masses, or infiltrates resembling consolidated lung.5–9 Few patients (less than 10%) develop pleural effusions.6,7
LYMPHOMAS (NON-HODGKIN) OF B-CELL LINEAGE
Primary Pulmonary Marginal Zone Lymphoma
The most common primary lymphoma of the lung is marginal zone lymphoma (MZL) of MALT type arising from MALT of the bronchus, accounting for approximately 70% of cases.10 Mucosa-associated lymphoid tissue in the lung was first described in 1973,11 and is believed to be acquired as secondary long-term response to various antigenic stimuli such as smoking, immunologic disease such as Sjogren syndrome, rheumatoid arthritis, Hashimoto thyroiditis, systemic lupus erythematosus, or infections such as hepatitis C and human immunodeficiency virus (HIV).12–17 Most patients who developed MZL, as noted in a few series, were former or active smokers.10,18,19 However, MZL of lung has not been shown to be consistently associated with any infectious agents or specific autoimmune conditions. Primary MZLs at other sites have been shown to harbor site-specific clinical and morphologic differences, such as gastric MZLs are shown to be often associated with Helicobacter pylori infection, ocular adnexal MZLs are occasionally associated with Chlamydia psittaci, and MZLs of the salivary gland and thyroid are associated with Sjögren syndrome and Hashimoto thyroiditis, respectively.4 The t(11;18)(q21;q21) chromosomal translocation, resulting in the production of a fusion protein composed of the apoptosis inhibitor API2 on chromosome 11q21 and the paracaspase MALT1 on chromosome 18q21, is the most common structural abnormality identified in the primary pulmonary MZL.20 Other translocations [t(14;18)(q32;21), t(1;14)(p22;q32), and t(3;14)(p14;q32)], as well as trisomies 18 and 3, have also been described in a subset of cases in other sites.21
MZL almost exclusively affects adults, although rare cases in younger patients have been reported.17,22 Patients with MZL may present with cough, fever, or unexplained weight loss, although many are entirely asymptomatic. The most common radiologic findings are presence of solitary or multiple discrete nodules or areas of consolidation that may occupy one or both lungs in either perihilar or peripheral distribution.8,9,23,24 Air bronchograms are common.5–9 These patients often present clinically with monoclonal gammopathy, with the most commonly reported paraprotein being immunoglobulin (Ig) M isotype.14 Recently, most patients have been diagnosed by minimally invasive procedures, including bronchial and transbronchial biopsies and computed tomography–guided percutaneous transthoracic biopsies, in contrast with the past, when open lung biopsy was often needed to confirm the diagnosis.23,25
Grossly, the lesions are gray, tan, solid, poorly defined masses with a firm, fibrous, or granular cut surface. These lesions show a peculiar distribution of tumor cells accentuated along bronchovascular bundles, interlobular septa, and visceral pleura. These lymphangitic infiltrates eventually coalesce into masses that can efface the lung parenchyma and form nodules or display a diffuse pattern (Figure 1, a). Invasion of bronchi, blood vessels, and pleura can also be seen. Most cases have interspersed intact or disrupted reactive lymphoid follicles. Presence of lymphoepithelial lesions, defined by the infiltration and distortion of epithelial structures by aggregates of (usually 3 or more) neoplastic lymphoid cells, is an important diagnostic feature in MZL (Figure 1, b).26 Anti-cytokeratin antibody, along with CD20/CD19 and CD5 antibodies, can facilitate identification of the lymphoepithelial lesions, highlighting marginal zone B cells in these areas. However, presence of lymphoepithelial lesion in the lung is not diagnostic of MZL, as these lesions can be seen in other conditions, such as autoimmune disorders, HIV infections, follicular bronchiolitis, and lymphoid interstitial pneumonia. The neoplastic cells are morphologically described as showing a spectrum of monocytoid, centrocyte-like, or lymphoplasmacytic cytology and occasionally appearing as large transformed B lymphocytes. Plasma cells containing Dutcher bodies can also be seen. The immunophenotype of the neoplastic cells of MZL is positive for pan–B-cell antigens CD19, CD20, PAX-5, IgM (> IgA > IgG), and occasionally CD43, and negative for IgD, CD5, CD10, CD23, terminal deoxynucleotidyltransferase, BCL-6, and cyclin D1. Plasma cells may be monotypic or polytypic. Flow cytometric immunophenotyping demonstrating the presence of a monoclonal B-cell population aids in the diagnosis of clonality. Immunoglobulin gene rearrangement studies may confirm the diagnosis.21
Pulmonary MZL can be associated with prominent stromal deposition of amyloid in 1% to 6% of cases.14,27 These are more commonly seen in older women with a median age of 70 years, and few of such patients have a history of autoimmune disease.28,29 Otherwise these patients have clinical, radiologic, histologic, and immunophenotypic features similar to those of pulmonary MZL without amyloid. The amyloid deposition can be randomly distributed in the stroma, or form large masses around blood vessels and bronchioles. They usually have a prominent plasma cell component, and can be associated with foreign body giant cell reaction, calcification, and ossification. It is important to note that the pathologist should not overlook the lymphoproliferative neoplasm in the setting of prominent amyloid deposition, especially on a small biopsy. Pulmonary MZL with light chain deposition disease has also been reported in an HIV-positive male.30 Light chain deposition disease shows deposits similar to amyloid, but these are Congo red negative, whereas amyloid has characteristic Congo red positivity. However, light chain deposition disease has granular appearance on electron microscopy compared with fibrils in amyloid.
Some cases of MZL may resemble pulmonary nodular lymphoid hyperplasia, but the latter shows polymorphous population of lymphoid cells (both B and T cells), confirmed by immunohistochemistry. In contrast, MZL shows predominance of B cells with more distinct morphology of marginal zone cells in a diffuse pattern, and in some cases coexpression of CD43 by B cells is present. If the lesion has many polytypic plasma cells, fibrosis, and vascular involvement by lymphoid infiltrate, IgG4-related sclerosing disease should be considered in the differential diagnosis. Staining for IgG4 and IgG should be performed, and a higher ratio of IgG4-positive plasma cells to IgG-positive plasma cells in combination with increased serum levels of IgG4 would support a diagnosis of IgG4-related sclerosing disease. Small biopsies can also be misinterpreted as lymphoid interstitial pneumonia; however, MZL tends to efface normal structures and does not show the predominant interstitial localization associated with lymphoid interstitial pneumonia.
Patients with pulmonary MZL usually have limited disease and follow an indolent clinical course with favorable outcome.1,18,19 These patients do require long-term follow-up and repeated biopsies and may develop relapses in the lung and in other MALT sites, and some may undergo transformation to diffuse large B-cell lymphoma. The optimal management of pulmonary MZL with regard to surgical resection, chemotherapy, or radiotherapy, alone or in combination, is not well established. Better progression-free survival has been observed with chlorambucil when compared with cyclophosphamide or anthracyclin in a study from Europe.25 Rituximab is a promising therapy used in these patients more recently.10,31 Prospective studies are needed to further evaluate different therapeutic regimens in these patients.
Primary Pulmonary Diffuse Large B-Cell Lymphoma
Primary pulmonary diffuse large B-cell lymphoma is the second most common type of primary pulmonary lymphoma, accounting for approximately 12% to 20% of cases.6,7,32,33 It commonly affects adults in the sixth and seventh decades of life. Patients usually present with cough or dyspnea and rarely hemoptysis. These neoplasms can be seen in both immunocompromised and immunocompetent patients. A subset of these lymphomas arise by transformation of preexisting or concurrent MZL, small lymphocytic lymphoma, and follicular lymphoma.34 The radiologic appearance is similar to that of MZL, except that pulmonary diffuse large B-cell lymphoma may have areas of necrosis, giving rise to cavitation.7
On gross examination, the tumor has a solid appearance with variable areas of necrosis. Primary diffuse large B-cell lymphoma in the lung forms confluent sheets of tumor cells and tends to destroy the normal lung parenchyma (Figure 2, a). The tumor is composed of large, dyscohesive tumor cells with coarse chromatin, distinct nucleoli, and abundant amphophilic cytoplasm (Figure 2, b). These are usually described as centroblastic or immunoblastic. The immunophenotype of the neoplastic cells is positive for CD19, CD20, and CD79a, and those of germinal center origin also express CD10 and BCL-6.
Among HIV-positive patients, nearly all cases have been diffuse, high-grade, Epstein-Barr virus (EBV)–positive B-cell lymphomas. Primary pulmonary lymphoma in these individuals seems to be related to severe immune deficiency and reactivation of latent EBV infection within the lung, as in AIDS-related primary central nervous system lymphoma.38 A rare case of EBV-positive pulmonary plasmablastic lymphoma in an HIV patient has been reported.39 HIV patients with pulmonary lymphomas have a poor prognosis usually secondary to opportunistic infections.
Differential diagnosis based on morphology alone includes primary or metastatic carcinomas, metastatic melanoma, and other epithelial malignancies. These are generally distinguishable by performing epithelial and hematopoietic immunohistochemical stains. Some cases of diffuse large B-cell lymphoma may have an increased number of T cells and are diagnosed as T-cell–rich large B-cell lymphoma. However, lymphoepithelioma-like carcinoma and HL should be ruled out in these cases. Diffuse large B-cell lymphomas are aggressive, but complete remission and long-term survival can be seen, with reported median survival time of approximately 8 to 10 years.1
Rare Non-Hodgkin Lymphoma of B-cell Lineage
Primary Pulmonary Plasmacytoma
Extramedullary plasmacytoma is known to comprise 4% to 6% of all plasma cell neoplasms. Solitary extramedullary plasmacytomas are plasma cell tumors that tend to develop in mucosa-associated lymphoid tissues including the sinonasal and nasopharyngeal regions and oral mucosa.40 Primary plasmacytoma of the lung is exceedingly rare, although pulmonary involvement with plasma cell myeloma is more common. Pulmonary plasmacytoma is seen in both sexes with equal predilection, and most of the patients are asymptomatic at presentation; however, symptoms like dyspnea, fever, and hemoptysis have been reported. Clinically it often presents as a solitary mass or nodule in lung or hilar areas. Diagnosis is confirmed by the presence of diffuse sheets of plasma cells that show monoclonality.41 Occasionally, the lesional cells are quite pleomorphic and would raise a differential diagnosis of bronchogenic carcinoma or metastatic melanoma. However, the amphophilic cytoplasm and paranuclear hof of plasma cells are quite helpful to make a correct diagnosis. All patients with plasmacytomas of lung should undergo complete evaluation for systemic plasma cell myeloma, including serum and urine electrophoresis, skeletal survey, and bone marrow evaluation. Flow cytometry analysis shows CD138 positivity in the plasma cells and restricted pattern of light-chain expression, which can be seen in the paraffin-embedded sections as well.
Unlike plasma cell myeloma, extramedullary plasmacytomas may not have serum M protein or Bence Jones light chains in urine. However, up to 25% of patients with extramedullary plasmacytoma will show a monoclonal gammopathy.42 Surgical resection is the best treatment for localized pulmonary plasmacytomas; it occasionally is combined with chemotherapy or radiotherapy.43 Plasma cell tumors are radiosensitive; however, the number of therapeutic options is reduced in patients with diffuse lung involvement, because surgery and radiotherapy are not feasible. Diffuse pulmonary plasmacytoma can be controlled effectively through a combination of chemotherapeutic agents. The prognosis of these patients is generally better than that of patients with systematic plasma cell myeloma. Extramedullary plasmacytoma can develop into systemic myeloma in a very few cases.40
Lymphomatoid granulomatosis (LYG) is an angiocentric and angiodestructive process that commonly affects the lung as bilateral nodular infiltrates, mimicking Wegener granulomatosis both clinically and radiographically. It is a disease that commonly affects adults in the fifth to sixth decade of life. It has a slight predisposition for males, with a male to female ratio of 2:1.44 It has been shown to be associated with EBV infection, with many cases arising in the setting of immunodeficiency.
The clinical features of LYG reflect systemic multiorgan disease. Pulmonary involvement usually is present, whereas the skin (50%), nervous system (25%), kidneys, and liver are affected less commonly, and late in the course of illness. Establishing the diagnosis of lymphomatoid granulomatosis usually requires an open lung or video-assisted thoracoscopic biopsy; because of the focal nature of lymphomatoid granulomatosis and the fact that it is not bronchocentric, a low diagnostic yield with bronchoscopic or transbronchial biopsies is likely.45
Recent World Health Organization (WHO) classification has characterized lymphomatoid granulomatosis as a B-cell neoplasm.59 Histologically, the tumor shows a nodular replacement of the lung parenchyma by a mixed mononuclear cell infiltrate with prominent vascular invasion and areas of necrosis surrounded by a rim of viable cells. The infiltrating cells show a varying number of small lymphocytes, histiocytes, plasma cells, and large transformed lymphocytes, which, at the high-grade end of the spectrum, occur in sheets, and are indistinguishable from diffuse large B-cell lymphoma. The large cells are CD20+, CD79a+, CD30+/−, CD15−, and EBV+, whereas the small lymphocytes are mostly T cells (CD4 > CD8).
Grading of LYG according to WHO 2008 criteria59 depends on the proportion of large B cells stained with EBV by in situ hybridization: grade 1 is composed of a polymorphous infiltrate with only a few large cells and fewer than 5 EBV-positive cells/high-power field, whereas grade 3 shows numerous large B cells, necrosis, and EBV-positive cells (>50/high-power field). Lymphomatoid granulomatosis of all grades is angiocentric, with accumulation of viable cells around the vessels, followed by angiodestruction, vascular invasion, luminal occlusion, and disruption of the vessels. Although the 2008 WHO criteria for classification of LYG are clear, there are some cases that do not fulfill all of the criteria. For practical purposes, Katzenstein et al46 have proposed the following criteria for LYG in a recent review: (1) mixed mononuclear cell infiltrate containing large and small lymphoid cells, often along with plasma cells and histiocytes, which replaces the lung parenchyma and shows vascular infiltration; and (2) variable numbers of CD20-positive large B cells, often with atypia, present in a background of CD3-positive small lymphocytes. The other supportive findings include areas of necrosis, positive in situ hybridization for EBV-encoded RNA, and multiple lung nodules radiologically, as well as skin or nervous system involvement.46
Although Wegener granulomatosis shows similarity to LYG clinically, radiologically, and somewhat histologically, it lacks the large CD20-positive B cells and contains large areas of basophilic necrosis with true granulomas and multinucleated giant cells. Other conditions in the differential diagnosis include viral pneumonia and bronchocentric granulomatosis, which lacks the angiocentricity and lymphocyte rich-population, and other lymphomas including HL, T-cell–rich B-cell lymphoma, peripheral T-cell lymphoma, and NK/T-cell lymphoma. The lymphoid neoplasms in the differential diagnosis can be distinguished from LYG by the lack of atypical large CD20-positive cells and presence of immunophenotypes characteristic of each subtype. The course of LYG patients has been described as usually progressive.45 In the large studies, mortality rates range from 63% to 90% at 5 years. Treatment for LYG has varied according to grade; grade 3 is presently treated as diffuse large B-cell lymphoma, and shows a prognosis roughly similar to that of diffuse large B-cell lymphoma.47 Lymphomatoid granulomatosis is a rarely diagnosed disorder; hence, it is difficult to accumulate more cases for more extensive studies and specific characterization.
Posttransplant Lymphoproliferative Disorder
Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ and hematopoietic stem cell transplantation that is linked to immunosuppression, EBV, and cytomegalovirus. Although PTLD has been described after transplantation of all solid organs, its incidence varies depending on the organ transplanted. Lung transplant recipients show an incidence between 2.5% and 8%.48 The higher risk of graft rejection occurring in lung transplant patients is partly explained by the increased immunosuppressant requirements for lung transplantation compared with other transplanted organs. Most patients have systemic involvement at presentation, but some patients may have disease confined to the allograft itself.49
Posttransplant lymphoproliferative disorder is a highly variable disease in its clinical presentation as well as in its pathologic characteristics. It can vary from simple lymphoid hyperplasia to aggressive lymphoproliferative neoplasm. Pathologically, there are 2 major subtypes of PTLD. Polymorphic PTLD is characterized morphologically by a plethora of monoclonal B cells in all stages of maturation as well as reactive T cells. Monomorphic PTLD is a subtype of non-Hodgkin lymphoma that appears as homogeneous sheets of transformed, monoclonal B cells, often with cytogenetic abnormalities. Regardless of the histologic features, the lymphoid cells in most cases of PTLD contain EBV detected by immunohistochemistry or in situ hybridization. T-lineage PTLDs, specifically of the γδ T-cell phenotype, although rare, can also occur after solid organ transplantation.50 Classifying the PTLDs into morphologic and molecular categories plays an important role in initial treatment planning and prognosis, and it is important to recognize that transplant patients can develop lymphomas of any subtype.51
The etiologic factors that underlie these different subtypes, as well as the implications for differential therapy and survival, are unknown.52 Disease in the thorax and involvement of the allograft are common in the first year after transplantation, but other sites, especially the gastrointestinal tract, predominate later.53 A systematic multidisciplinary (clinical, radiologic, virologic, and histologic) approach is mandatory for the diagnosis and management of PTLD in lung transplant recipients. In addition, staining for EBV antigens and quantification of EBV DNA in biopsy specimens should always be performed to understand the role of EBV infection in the pathogenesis of PTLD.54
LYMPHOMAS OF T-CELL LINEAGE
Peripheral T-Cell Lymphoma
Primary pulmonary peripheral T-cell lymphoma is an extremely rare and aggressive disease and is mostly found as case reports in the literature.55,56 These patients are often clinically ill and may present with fever, cough, and dyspnea. The clinical course is usually aggressive, and relapses are more common for T-cell lymphoma than for the B-cell lymphomas. Patients with peripheral T-cell lymphoma are usually adults with generalized disease; the lymph nodes, liver, and spleen may be involved. It is more commonly seen in males.57 A few case reports of primary pulmonary T-cell lymphoma in HTLV-1 carriers have also been reported.55 The incidence of primary pulmonary T-cell lymphoma is higher in the Asian population than in the Western population, as is the case with T-cell lymphomas in general.56
The radiologic findings are similar to those associated with pulmonary MZL and consist mainly of ground-glass attenuation, centrilobular nodules, thickening of bronchovascular bundles, reticular shadows, and interlobular septal thickening in the peripheral lung.55,57,58 The WHO has divided the mature T-cell neoplasms into specifically defined entities.59 The cases that do not match one of the defined entities of peripheral T-cell lymphoma are best categorized as “not otherwise specified,” reflecting that we do not yet fully understand the underlying pathogenesis.
Histologic examination of the lung shows diffuse infiltrates of large lymphoid cells with pleomorphic, vesicular nuclei; prominent nucleoli; and frequent mitoses (Figure 3, a and b). Rare cases also show predominance of small lymphoid cells with atypical, irregular nuclei. Angiocentricity is often seen in these neoplasms. Immunohistochemical staining demonstrates tumor cells with aberrant T-cell phenotype that are positive for CD3 with frequent down-regulation of CD5 and CD7 and are negative for CD20, CD30 (Ki-1), and CD56. The Ki-67 proliferative index is usually high in these neoplasms, exceeding 70%. Peripheral T-cell lymphoma shows clonal T-cell receptor gene rearrangements by polymerase chain reaction analysis in most cases. Most of the cases of primary pulmonary T-cell lymphoma reported in the literature were diagnosed by open lung biopsy. These patients receive chemotherapy, often with poor response.57 In our experience, the diagnosis of this type of lymphoma is difficult, and it is important to keep this entity in differential diagnosis when the specimen shows neoplastic cells that are CD3 positive. It is recommended to further investigate these specimens for immunophenotyping and molecular genetics. Making a timely diagnosis and starting the patients on therapy earlier can perhaps prevent the fatal outcome seen in most patients.
Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma (ALCL) has a propensity to involve extranodal sites, particularly skin and rarely other extranodal sites such as lung. Primary pulmonary ALCL has been reported in the literature as case reports only.2,60 Patients with ALCL have a bimodal age distribution seen in children61 and adults, with male predominance. Anaplastic large cell lymphoma has an aggressive clinical course, and patients frequently present with systemic symptoms and advanced-stage disease. The tumor cells express a T-cell phenotype, and rarely may also have a null phenotype. Anaplastic large cell lymphoma is characterized by diffuse sheets of large cells with pleomorphic nuclei and abundant cytoplasm. The nuclear chromatin is usually finely clumped or dispersed with multiple small, basophilic nucleoli. A majority of these cells are positive for a pan–T-cell marker such as CD2, CD3, or CD45RO, although null phenotype may be negative for these markers. Consistent expression of CD30/Ki-1 is an important hallmark of this disease. Most cases express cytotoxic granule-associated proteins such as TIA1, granzyme, and/or perforin. Anaplastic large cell lymphoma may mimic metastatic carcinoma or melanoma on morphology; thus, performing a battery of hematopoietic and epithelial markers is obligatory as a diagnostic aid. A few studies from the literature suggest that the risk of progression to systemic disease and death is high in patients who present with primary pulmonary ALCL.62
Anaplastic large cell lymphoma should be distinguished from other T-cell large cell lymphomas by its reactivity with anaplastic lymphoma kinase (ALK) immunostain or by presence of t(2;5) translocation involving the NPM and ALK genes. However ALCL (ALK negative) is included as a provisional entity in the recent WHO classification.
NK/T-cell lymphoma is characterized by vascular destruction, prominent necrosis, and associated EBV infection. It is more prevalent in Asians and in the Native American populations of Mexico and Central and South America. The most frequent presentation of this tumor is extranodal, usually in the upper aerodigestive tract; other sites of involvement are skin, soft tissue, gastrointestinal tract, testis, and spleen. Rare cases with isolated lung involvement have been reported.63 Patients often present with systemic symptoms and advanced stage, with involvement of multiple sites. The tumor cells show an angiocentric and angiodestructive pattern with a broad cytologic spectrum. The major immunophenotype of these neoplasms includes positivity for CD2, CD56, and cytoplasmic CD3, and negativity for surface CD3. NK/T cell lymphoma occurring outside the nasal cavity is a highly aggressive neoplasm with poor response to therapy and short survival time.
SECONDARY PULMONARY NON-HODGKIN LYMPHOMA
Lung is a relatively frequent site of secondary involvement of lymphoma; this is more common in patients with HL (approximately 38% of cases) as compared with non-Hodgkin lymphoma (approximately 24%).64,65 These patients have prior or concurrent nodal lesions of lymphoma or develop evidence of systemic lymphoma up to 6 months after presentation. Secondary involvement may result from direct mediastinal node extension or from lymphatic or hematogenous dissemination from distant sites. Nodules, masses, and consolidation with diffuse ground-glass opacities are common radiologic pulmonary manifestations of secondary involvement of the lung by lymphoma. Mediastinal lymphadenopathy and pleural effusion are also commonly present.66,67 Patients usually present with nonspecific pulmonary symptoms. A high suspicion of lung involvement by lymphoma should be considered if a patient with a prior history of lymphoma develops lung lesions; further extensive workup with correlation of clinical, microbiologic, and histologic findings is necessary in these cases. Diagnosis of secondary pulmonary lymphomas is made using the same criteria as in the evaluation of lymph node biopsies. These patients are staged using the Ann Arbor criteria, and their prognosis is determined by both stage and histologic subtype.
Follicular lymphoma, small lymphocytic lymphoma, and mantle cell lymphoma are the most common systemic B-cell lineage lymphomas to secondarily involve the lung. MZL frequently involves the lung secondarily after presentation in other mucosal sites. Clinical history, morphology, and immunohistochemical studies are necessary to provide an accurate diagnosis and classification for all of these cases. If the clinical history is known at the outset, sending tissue for flow cytometric analysis can provide accurate timely diagnosis and classification.
The vast majority of patients with T-cell lymphomas have systemic disease at presentation. Clinical history and histologic, immunophenotypic, viral, and cytogenetic analysis all contribute to diagnosing specific subtypes of lymphoma, including T-cell prolymphocytic leukemia, angioimmunoblastic-type peripheral T-cell lymphoma, and T-cell ALCL. About 10% of patients with peripheral T-cell lymphoma have pulmonary involvement.66
HODGKIN LYMPHOMA IN THE LUNG
Primary pulmonary HL is a rare entity.68–71 Hodgkin lymphoma is most commonly seen in the lung as secondary involvement. Hodgkin lymphoma affects young adults with a mean age of 42 years and with slight female predisposition. These patients present with single or multiple parenchymal masses, endobronchial lesions, or pneumonia-like consolidation. It is difficult to diagnose HL in lung, especially on scant endobronchial tissue or transthoracic needle biopsies or in frozen sections, because of the lack of identification of Hodgkin cells or Reed-Sternberg cells in a small sample. The diagnosis of HL in lung is based on the recognition of diagnostic Reed-Sternberg cells within the appropriate reactive cellular infiltrate in the background (Figure 4, a and b). Nodular sclerosis and mixed cellularity are the common histologic types seen. Differential diagnoses for classic HL include solitary fibrous tumor with extensive inflammation and inflammatory myofibroblastic tumor. Immunohistochemically, the tumor cells are positive for CD15, CD30, Pax5, and rarely CD20, and negative for T-cell markers.21,72 Factors that correlate with a poor prognosis include age greater than 60 years, B symptoms, multiplicity and bilaterality of lung lesions, pleural effusion, and cavitation.73 It is suggested that chemotherapy is recommended over radiotherapy in this disease because of the risk of radiation pneumonitis.
LYMPHOMAS OF THE PLEURA AND PLEURAL CAVITY
Pleural involvement by a lymphoma can be seen secondary to systemic disease or intraparenchymal disease. Pleural cavity can be involved by virtually any subtype of lymphomas. Diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma arising primarily in the pleura have been described in the literature.74,75 There are 2 distinct types of primary pleural lymphomas described: primary effusion lymphoma and pyothorax-associated lymphoma.59
Primary effusion lymphoma is a rare distinctive type of diffuse large B-cell lymphoma characterized by lymphomatous effusion of pleural, pericardial, or peritoneal cavities, without any solid mass.76 Nearly all patients are HIV-positive young adults; males are affected much more often than females. These neoplasms are human herpesvirus 8 positive and can also be coinfected with EBV. The neoplastic cells are very large, uniform, and pleomorphic (immunoblast-like), and some may resemble Reed-Sternberg cells. Neoplastic cells express CD45 and are negative for B-cell antigens. However, immunoglobulin light and heavy chains are clonally rearranged, supporting a B-cell lineage. Primary effusion lymphoma frequently is associated with mutations in the 5′ noncoding regions of BCL6 as well as the immunoglobulin gene variable regions. These patients have a poor prognosis.
Pyothorax-associated lymphoma is a rare EBV-positive diffuse large B-cell lymphoma arising in patients with long-standing chronic pyothorax (treated with iatrogenic pneumothorax), secondary to tuberculosis. Patients present with a mass in the pleura accompanied rarely by lung mass or pleural effusion. On microscopic examination, the tumor shows diffuse proliferation of large atypical cells, with centroblastic and/or immunoblastic or plasmacytoid features with areas of necrosis. Neoplastic cells express pan–B-cell antigens and MUM1; rarely are CD138 positive; and are negative for CD10, bcl-6, and human herpesvirus 8. These patients have a dismal prognosis.
EXPERIENCE AT NORTHWESTERN UNIVERSITY (10-YEAR RETROSPECTIVE REVIEW)
Of approximately 1500 patients with lung neoplasms diagnosed in the last 10 years at our institution, 64 patients (approximately 4%) were diagnosed with lymphoproliferative neoplasms; 25 patients (1.7%) were diagnosed with primary pulmonary lymphomas and 39 (2.7%) with secondary involvement of the lung. The mean age, male to female ratio, mode of diagnosis, and subtype of lymphomas diagnosed are depicted in the Table. Twenty patients had a history of immunosuppression, including HIV, Epstein-Barr virus, Crohn disease, history of transplant, and epithelial neoplasms. Flow cytometry analysis and molecular studies were performed in 65% of cases. Only 2 cases were difficult to classify according to the recent WHO classification. Surgical lung biopsies and bronchoscopic biopsies in conjunction with flow cytometry and molecular studies were efficient modalities to diagnose primary pulmonary lymphoma and secondary involvement of the lung in our series. Lymphomatoid granulomatosis, diagnosed more commonly in the past, is rare in our series owing to the utility of molecular and flow cytometric analysis to make a definitive diagnosis of clonal population. Rare lymphomas such as peripheral T-cell lymphoma, ALCL, and PTLD should also be considered in the differential diagnosis of the lymphoid neoplasms primarily involving the lung.
In the past 15 to 20 years, pulmonary lymphomas have become better defined entities with the help of advanced technology. Marginal zone lymphoma stands out as the best example in this category. It is presently a well-defined lymphoma and constitutes the largest group of pulmonary lymphomas with an overall good prognosis. Lymphomatoid granulomatosis entity is also better understood and belongs in the group of lymphoproliferative neoplasms, and is considered by most as an EBV-driven B-cell neoplasm. There is also evidence that the more rare subtypes of lymphoma, including T-cell, NK cell, and ALK-positive lymphomas, may also occur as primary neoplasms in the lung, and a timely diagnosis and treatment is necessary in an attempt to improve patient survival rates.
The authors have no relevant financial interest in the products or companies described in this article.