Lymphoproliferative disorders of the lung and pleura comprise a varied but rare group of localized and diffuse processes that span the morphologic gamut from reactive to neoplastic and include several peculiar lesions that do not fit conventional definitions of either hyperplasia or neoplasia. Although most diagnoses are based on light microscopy, immunohistochemical and molecular investigations have assumed a vital role. Nomenclature and classification schemes have undergone drastic changes over the past quarter century and current definitions appear reasonable. Malignant lesions are best classified according to the current World Health Organization (WHO) scheme.1 This chapter presents the clinicopathologic features of primary and secondary pulmonary and pleural hematolymphoid lesions.
Anatomy and Histology of the Pulmonary Lymphoid System
Pulmonary lymphatics are divided into two interconnecting channels that drain to peribronchial, hilar, and/or mediastinal lymph nodes and eventually into the thoracic duct, right lymphatic duct, and subclavian veins.2 One system drains through the visceral pleura around the lung into mediastinal lymph nodes and the other drains from central lung parenchyma to peribronchial and hilar lymph nodes. The lymphatics communicate at lobar, lobular, and pleural boundaries and thus serve each other as potential collaterals.3,4 Although not usually obvious in histologic sections of normal lung, lymphatics are prominent in disease states ranging from pulmonary edema to lymphangitic carcinoma. In the latter, lymphatic channels distended with malignant cells are apparent within the visceral pleura, interlobular septa, and adventitia of arteries, veins, and bronchioles. Of note, alveolar septa do not contain lymphatic channels. All lymphatics contain valves and flat endothelial cells line the discontinuous basal lamina. Larger lymphatics contain smooth muscle and collagen.
Small submucosal aggregates of lymphoid cells are often prominent at bronchial bifurcations and near distal respiratory bronchioles (pulmonary microtonsils) and represent bronchus-associated lymphoid tissue (BALT) (Fig. 120-1).5–7 Whether humans are born with this specialized secondary lymphoid system, or whether the aggregates of B lymphocytes, T lymphocytes, HLA-DR+ interdigitating cells, follicular dendritic cells, and lymphoid follicles with overlying flattened and attenuated specialized epithelium develop in response to antigenic stimulation is controversial.8,9 Viruses, connective tissue disorders, tobacco use, and obstructive pneumonia are just a few pathologic processes known to induce BALT (Table 120-1). Unlike typical lymph nodes that rely on afferent lymphatics for antigen retrieval, BALT is integrated into lung tissue and antigen is sampled directly from the bronchial and bronchiolar lumens through specialized “lymphoepithelium.” Immunoglobulins, most notably IgA, are synthesized and secreted by lymphocytes directly into airway lumens. Amazingly, this system appears capable of mounting a competent adaptive immune response. In addition, BALT B-lymphocytes circulate and “home” to other mucosal sites such as the conjunctiva, salivary glands, stomach, and intestines to create a common mucosal immune system, the mucosa-associated lymphoid system (MALT).6 Thus, responses induced in one location can be replicated at other sites.10 Malignant lymphoma arising in one MALT location can secondarily involve other MALT sites. BALT appears to be the origin of many primary pulmonary lymphoid lesions.11
Bronchus-associated lymphoid tissue. The submucosal collection of lymphoid cells is intimately associated with overlying bronchiolar epithelium. Hematoxylin and eosin, 40× original magnification.
Table 120-1Diseases Associated with Hyperplasia of Bronchus-Associated Lymphoid Tissue ||Download (.pdf) Table 120-1Diseases Associated with Hyperplasia of Bronchus-Associated Lymphoid Tissue
|Autoimmune diseases |
Allergy such as asthma
Autoimmune hemolytic anemia
Primary biliary cirrhosis
Systemic lupus erythematosus
|Immunodeficiency syndromes |
|Drug-induced forms |
Intrapulmonary lymph nodes (IPLs) may be part of the pulmonary immune system and may also be induced by antigenic stimuli rather than normal embryologic development.12 Autopsy studies suggest a prevalence of 18%, and although many are related to bronchi of the first few orders, peripheral subpleural locations are not uncommon. In this age of high-resolution computed tomography (HRCT) and lung cancer screening programs, up to 80% of reported cases of IPLs occur in men with histories of tobacco use and almost 35% of cases are multiple.13 They appear as round to angulated sharply circumscribed subpleural opacities up to 2 cm in diameter and are found along interlobular septa or within major and minor fissures. IPLs histologically resemble classic lymph nodes with well-developed cortical and medullary areas.12,14 Sinus histiocytes frequently contain abundant anthracosilicotic pigment and silicotic nodules with calcifications may form (Fig. 120-2). In patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), IPLs may be involved and, rarely, primary lung carcinoma or carcinoma from a nonpulmonary site can metastasize to IPLs. Most importantly, IPLs can be clinically, radiographically, and cytologically mistaken for malignancy.15,16 Although fine-needle aspirates can exclude the possibility of carcinoma, an erroneous diagnosis of lymphoma might be considered.
Intrapulmonary lymph node. Subpleural lymph nodes often accumulate carbon pigment and become fibrotic. The radiologic differential diagnosis includes carcinoma, while a fine-needle aspirate sample may mimic malignant lymphoma. Hematoxylin and eosin, 4× original magnification.
Although internists, pulmonologists, and radiologists often diagnose pulmonary diseases on the basis of clinical and radiographic findings and rely on tissue samples merely for confirmation, lymphoid lesions of the lung are often unsuspected diagnoses rendered by pathologists. Yet clinical and radiologic studies are essential in the interpretation of all lesions. Often, light microscopic considerations can be excluded purely on the basis of radiographic findings. For example, whereas pulmonary lymphomas can be localized or diffuse, lymphoid interstitial pneumonia (LIP) is always bilateral and diffuse.
Although fine-needle aspirate biopsies and transbronchial biopsies supplemented with ancillary studies may suffice for a diagnosis of malignant lymphoma, architectural and cytologic variability necessitates generous sampling. Since cellular monotony is not the sole criterion for malignancy, pulmonary lymphoid lesions often require wedge biopsies for diagnosis. Whereas sheets of uniform cells may be diagnostic of lymphoma, many malignant processes such as Hodgkin lymphoma (HL) and T-cell lymphoma are polymorphous and admixed with inflammatory cells. Secondary changes and biopsy-related artifacts may also confound the interpretation of a small sample.
Larger samples also allow for low-magnification pattern recognition. A “lymphatic distribution” may be seen in nonlymphoid processes such as sarcoidosis, yet is most striking in lymphoproliferative lesions reflecting the homing of lymphoid cells to endogenous pulmonary lymphatic routes. Although malignant lymphoid processes usually obliterate underlying lung architecture, diffuse alveolar septal expansion with lymphoid cells without a beaded lymphangitic pattern tends to represent an inflammatory rather than neoplastic process.
In addition to histologic examination, immunophenotyping is routinely performed and has become indispensable in diagnosing and classifying lymphoid lesions of the lung. Immunohistochemical studies can be reliably performed on formalin-fixed, paraffin-embedded tissue, whereas flow cytometry is useful for demonstrating immunoglobulin light-chain restriction. Aberrant antigen expression by either method also allows for subclassification. Polymerase chain reaction (PCR) may be required in up to 20% of cases to prove clonality.17 Either rearrangement of the immunoglobulin heavy-chain gene joining region (JH) or the T-cell receptor γ-chain gene (TCR-γ) can be investigated. Lastly, chromosomal abnormalities indicative of specific lymphomas such as t(14;18) translocation and bcl-2 gene rearrangement in follicular lymphoma or t(11;14) translocation and cyclin D1 (bcl-1) gene rearrangement in mantle cell lymphoma may be helpful.
Given the complex evaluation required of these lesions, it is incumbent upon the clinician to deliver the fresh tissue sample to the pathologist along with his or her concern for lymphoma. Although formalin-fixed or B5 fixed, paraffin-embedded samples may suffice for diagnosis and immunohistochemical evaluation, cell suspensions and fresh frozen tissue are required for flow cytometry, cytogenetics, and many molecular studies.
Lastly, although clonality indicates malignancy, clonality in pulmonary lymphoid lesions may not predict clinical outcome. Many pulmonary lymphomas have long indolent courses with 10-year survival rates of more than 80% yet LIP, a polyclonal process, is progressive with one-third of affected patients dying of end-stage pulmonary fibrosis.18,19
Reactive Lymphoid Processes
Although the terminology used to describe inflammatory processes of the lung has remained relatively static over the past 25 years, immunohistochemistry and molecular genetic analysis have redefined diagnostic criteria. Processes arising from BALT include nodular lymphoid hyperplasia (NLH), follicular bronchitis/bronchiolitis (FBB), diffuse lymphoid hyperplasia (DLH), and LIP. Pulmonary hyalinizing granuloma (PHG) is included in this section for historical reasons only. Although the lesions are best considered either localized or diffuse, clinicopathologic entities including Castleman disease (CD) can manifest with either distribution.
Localized Reactive Lymphoid Processes
Localized reactive lymphoid processes, including nodular lymphoid hyperplasia, pulmonary hyalinizing granuloma, amyloidosis, and light chain deposition disease are discussed below.
Nodular Lymphoid Hyperplasia
Known to previous generations of pulmonologists and hematopathologists as “pseudolymphoma,” this reactive process was recognized as a form of BALT hyperplasia in the mid-1980s.20 Although NLH was once considered to be quite common, ancillary studies have convincingly demonstrated that most cases were actually low-grade lymphomas.21 Thus true NLH is now considered a legitimate but exceedingly rare polymorphous nodular lymphoid lesion of the lung.22 Neutrophilic microabscesses and foreign body giant cells found in several reported cases indicate that the lesion may be the result of an inflammatory stimulus. Interestingly, immunohistochemical studies have documented B-cell lymphomas of BALT within pre-existing reactive masses of BALT, such that one could, in the most general sense, consider NLH a precursor lesion.11,20
Most affected individuals are middle aged with a nearly equal gender incidence.22,23 Patients are usually asymptomatic, although a small percentage may have autoimmune diseases such as systemic lupus erythematosus or Sjögren syndrome, or polyclonal hypergammaglobulinemia. Lesions usually appear as solitary subpleural radiographic nodules with air bronchograms, but several nodules or localized infiltrates can be seen, the latter finding serving as a reminder that the distinction between nodular and diffuse processes is arbitrary.24 Up to one-third of cases feature regional lymphadenopathy.
Excised tan-white rubbery to firm nodules measure from 0.6 to 6.0 cm. Histologically, the well-demarcated lesions may feature slight extension along alveolar septa and central scarring. Normal lung parenchyma is overrun by large reactive germinal centers with well-preserved mantle zones, and lymphoepithelial lesions are not seen (Fig. 120-3). Interfollicular areas are filled with plasma cells and mature lymphocytes. The follicles are clearly reactive with a variety of cell types, mitoses, and macrophages. Regional lymph nodes often feature reactive follicular hyperplasia.
Nodular lymphoid hyperplasia. The lesion is composed of benign reactive germinal centers. Although radiographically nodular, germinal centers spill out into surrounding lung. Immunohistochemistry is required to exclude a diagnosis of malignant lymphoma. Hematoxylin and eosin, 1× original magnification.
Immunohistochemical studies demonstrate a mixture of B- and T-cells. The B-cells express both κ and λ light chains, that is, lack light chain restriction. Aberrant B-cell staining for CD5, CD23, or CD43 is not seen, and the germinal centers do not stain with bcl-2.22,25 Immunoglobulin heavy chain gene rearrangement or evidence of t(14;18) breakpoints is not observed. These ancillary findings are of the utmost importance since light microscopy alone may not differentiate NLH from an extranodal marginal zone B-cell lymphoma of MALT. The latter usually features infiltrative growth, but may have reactive follicles and polytypic plasma cells with only a focal monotypic cell population.
Surgical excision is usually curative, although a small percentage of patients develop local recurrences at the original surgical site. Neither systemic spread nor death has been reported.22,25
Pulmonary Hyalinizing Granuloma
PHG is neither a lymphoid nor granulomatous lesion per se, but an ever-present lymphoid component allows for its discussion in a hematolymphoid chapter. This peculiar fibrosing process shares clinicopathologic and morphologic features with sclerosing mediastinitis, inflammatory pseudotumor of the orbit, Riedel thyroiditis, and idiopathic retroperitoneal fibrosis.26 In fact, approximately one-fourth of cases feature concomitant mediastinal or retroperitoneal disease.27,28 The etiology is unknown but it has been speculated to represent either an autoimmune phenomenon or exaggerated host response to mycobacteria or fungi.
Age at presentation ranges from 24 to 77 years and women are affected twice as often as men. Most patients present with mild symptoms including cough, shortness of breath, fever, and fatigue but up to 25% of reported individuals are asymptomatic. Laboratory studies include positive antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, and Coombs-positive hemolytic anemia.28 Elevated serum or tumor immunoglobulin G4 (IgG4) levels are rarely reported.29,30 Skin testing often demonstrates exposure to Mycobacterium tuberculosis or Histoplasma capsulatum, but cultures and stains for microbes are negative. Radiographs reveal less than 4.0 cm bilateral and multilobar ill-defined homogeneous nodules that resemble metastases.31 Unilateral and solitary cases measuring up to 15 cm have been reported. Although not common, focal central irregular calcification may suggest metastatic bone-forming neoplasms. Central cavitation is rare.
Lesions are sharply circumscribed white-tan rubbery masses composed of irregular concentric whorls of hyalinized collagen encasing vessels and airways (Fig. 120-4A).27,28 The center of the lesion is paucicellular, whereas peripheral thick collagen bands are separated by mature T-lymphocytes, plasma cells, fibroblasts, and occasional giant cells (Fig. 120-4B). Blood vessels may feature transmural inflammation without necrosis. Microscopic calcifications can be seen, but granulomas are not present despite the designation PHG. The tumoral interface with lung parenchyma features reactive germinal centers, whereas adjacent lung may feature organizing pneumonia and hyperplasia of BALT. The morphologic differential diagnosis includes rheumatoid nodule, amyloidosis, granulomatosis with polyangiitis (Wegener granulomatosis), malignant lymphoma, inflammatory myofibroblastic tumor, and infections.29 Clinicians should not be comfortable with a diagnosis of PHG rendered on anything less than a completely removed lesion.
Pulmonary hyalinizing granulomas. A. Multiple well-circumscribed tan firm nodules can compromise respiratory function. B. Pink hyalinized collagen bands encircle vessels. Scant benign lymphoid infiltrates percolate between the collagen. Hematoxylin and eosin, 10× original magnification.
PHG tends to enlarge slowly and does not recur after surgical resection. However, growth of unresected or unresectable nodules can lead to respiratory compromise.28
Amyloidosis and Light Chain Deposition Disease
Immunoglobulin light chains can accumulate in many tissues in different forms, depending on the underlying condition and particular organ cytoskeleton. Clinically recognizable disease in the lung can manifest as tracheobronchial disease, solitary or multiple nodules, cystic lung disease, or in a diffuse interstitial parenchymal pattern.32,33 Most cases of diffuse light chain deposition in the lung are part of multiorgan involvement, are associated with plasma cell dyscrasia, have dismal clinical outcomes, and are not discussed further in this section.
Solitary and multiple amyloidoma are seen most often in older individuals, with a mean age of 67 years.32 Central and solitary lesions are often incidental findings but airway or visceral pleural distortion may produce cough, hemoptysis, or pleuritic chest pain. A radiographic diagnosis can be suggested when calcification or ossification is noted (20%–50% of the time); otherwise, the clinical impression is that of a neoplasm.34
Serum or urine monoclonal proteins are found in 10% of patients, and this lung pathology may be associated with lymphoproliferative diseases such as benign monoclonal gammopathy of undetermined significance, Sjögren syndrome, Crohn disease, NLH, LIP, extranodal marginal zone B-cell lymphoma of MALT, or multiple myeloma.32,35–37 Solitary amyloidoma without underlying blood dyscrasias probably represent a hyperimmune response to unknown antigens.
Waxy hard gritty and yellow-tan nodules measure up to 15 cm and are composed of amorphous eosinophilic hyaline material that obliterates lung parenchyma but spares many arterioles (Fig. 120-5). Lymphocytes, plasma cells, and multinucleated giant cells percolate through the amyloid, but the infiltrate is most dense at the periphery of the nodules. Calcification and ossification with secondary marrow space formation is common. Congo red staining examined by polarizing microscopy reveals lesional apple-green birefringence. Immunohistochemical studies usually demonstrate λ light-chain composition and negative immunoreactivity for amyloid A and transthyretin.37,38 Plasma cells are most often polytypic; however, small foci of monoclonal plasma cells within foci of polytypic plasma cells have been identified.39 Ultrastructurally, amyloid is composed of disorderly nonbranching hollow-core 8- to 10-nm fibrils. These extracellular deposits of chemically diverse proteins form a three-dimensional twisted β-pleated sheet. Resected lesions may not demonstrate malignancy, but patients should be screened for underlying monoclonal B-cell proliferations including multiple myeloma and overt B-cell malignancies.
Nodular amyloidosis. Amorphous pink material replaces air spaces and overruns airways. In the absence of Congo red apple-green birefringence one should consider the possibility of nodular light chain deposition. Hematoxylin and eosin, 4× original magnification.
In stark contrast to nodular amyloidosis, pulmonary light chain deposition disease (LCDD) is associated with an underlying blood dyscrasia or renal failure in more than 50% of affected individuals.40–42 Most patients have free κ monoclonal light chains (IgG, IgA, and IgM in decreasing order) in their urine or serum.43 The clinical and light microscopic appearance of LCDD is similar to amyloid, and one might mistake a case lacking the characteristic Congo red staining as simply a poorly stained example of amyloid. These light chain deposits are composed of amorphous granular or globular electron dense material.43 One should consider this entity when dealing with a nonamyloidotic deposit given its strong association with lymphoid malignancies including but not limited to multiple myeloma and renal failure.43,44
Diffuse Reactive Lymphoid Processes
Although NLH most likely represents a local response to an extrinsic stimulus and is clinically relevant owing to its radiographic appearance as a coin lesion and morphologic similarity with extranodal marginal zone B-cell lymphoma of MALT, the DLHs, FBB, and LIP represent a continuum of BALT hyperplasia often seen in patients with systemic diseases (Table 120-1).20,25,45 The extent of lung involvement is due in large part to host immune factors.46 Although thoracoscopic or open lung biopsies are required to establish these diagnoses and exclude other processes, including interstitial lung diseases and malignant lymphoma, morphology does not suggest etiology.
DLH restricted to the walls of airways and peribronchial tissue is referred to as FBB. FBB is often seen in individuals with bronchiectasis, chronic infections, and chronic obstructive pulmonary diseases, including asthma.45,47 The entity may also be seen in association with connective tissue diseases, congenital or acquired immunodeficiencies, or bone marrow transplantation; or as a manifestation of a hypersensitivity reaction.48,49 When the process spreads along lymphatic routes of the pulmonary lobule some prefer the designation DLH instead of FBB.
Patients with FBB in association with connective tissue disease are usually in their forties and most often suffer from rheumatoid arthritis (RA) or Sjögren syndrome.50,51 Patients with immunodeficiency syndromes such as acquired immunodeficiency syndrome (AIDS), common variable immunodeficiency, IgA deficiency, and Evans syndrome present in childhood, whereas those with hypersensitivity syndromes are usually in their sixth decade of life. Patients may also suffer with chronic low-grade infections such as mycoplasma, chlamydia, or Epstein–Barr virus (EBV).45
Individuals with FBB present with dyspnea, cough, and fever; some may have recurrent pneumonia or weight loss. Pulmonary function tests reveal restrictive, obstructive, or normal patterns.47 Those with RA often have a very high rheumatoid factor on the order of 1:640 to 1:2560. Peripheral eosinophilia may be noted in those with hypersensitivity syndromes. Arterial blood gases show arterial hypoxia with a widened AaPO2 gradient and hypocapnia. Chest radiographs feature bilateral diffuse reticular and nodular opacities, whereas HRCT show up to 12-mm centrilobular and peribronchial nodules with or without areas of ground-glass opacity.24,52
Gross pathology demonstrates numerous minute (1- to 2-mm) nodules adjacent to airways. Microscopically, nodular aggregates of B-cell rich lymphocytes and plasma cells with reactive germinal centers expand bronchial and/or bronchiolar submucosa and budge into and permeate overlying epithelium (Fig. 120-6). Rare T-cells wander beyond the follicles into adjacent alveolar septa.25 Smaller airway lumens are distorted and narrowed predisposing to mucostasis and subsequent infections. Lymphoid follicles along interlobular septa and beneath the pleura represent a more diffuse form of lymphoid hyperplasia and warrant the descriptive diagnosis DLH.
Follicular bronchitis/bronchiolitis. Reactive germinal centers expand airway submucosa and compress the lumen. Mucus accumulation often leads to infection and bronchiolectasis. Alveolar parenchyma is spared. Hematoxylin and eosin, 4× original magnification.
Treatment of FBB with corticosteroids has variable results.47,48 Those with peripheral eosinophilia are reportedly steroid responsive.
Lymphocytic Interstitial Pneumonia
Although LIP is included in the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias, this multifactorial but rarely idiopathic process represents the most florid form of BALT hyperplasia and may be difficult to differentiate from florid FBB and low-grade malignant lymphoma.53 Almost all patients with LIP have immunologic disorders, dysproteinemias, or viral infections, including EBV and, especially in children, human immunodeficiency virus (HIV).54–57 The age and sex distribution reflect these different populations. This clinicopathologic process is rare in the HIV-negative population, but represents a pulmonary manifestation of chronic graft-versus-host (GVH) disease in bone marrow transplant patients.54 A strong association with Sjögren syndrome is also noted.58 Most HIV-negative patients are middle-aged Caucasian women.
The clinical presentation includes cough and/or dyspnea in addition to symptoms and signs related to underlying diseases. More than 60% of patients have dysproteinemias, which can precede the onset of LIP or occur any time during the clinical course.54,59,60 Most of these cases are associated with hypergammaglobulinemia; only 10% of cases are associated with hypogammaglobulinemia. A monoclonal spike on serum immunoelectrophoresis suggests a diagnosis of lymphoma rather than LIP. Pulmonary function tests reveal reduced lung volumes and diffusing capacity for carbon dioxide (DlCO), and hypoxia is common.54 Bronchoalveolar lavage (BAL) analysis shows an increased percentage of lymphocytes. Chest radiographs demonstrate bilateral reticular and nodular opacities, ground-glass opacities, and parenchymal consolidation with lower lung zone predilection. Computed tomography demonstrates diffuse ground-glass opacities, ill-defined centrilobular nodules, bronchovascular and interlobular thickening, and scattered less than 3.0-cm thin-walled cysts.61–63
The lungs are typically firm and tan-gray and end-stage cases feature honeycomb change with subpleural cysts. Although the radiographs and gross appearance suggest parenchymal consolidation, histologically LIP shows a diffuse prominently interstitial infiltrate of small lymphocytes, plasma cells, larger mononuclear cells, and histiocytes (Fig. 120-7A). Although these infiltrates are centered on airways, vessels, and interlobular septa, and include peribronchiolar lymphoid follicles, infiltration into alveolar septa is always present and distinguishes LIP from FBB (Fig. 120-7B). Small nonnecrotizing granulomas, reactive germinal centers, and infiltration into overlying respiratory epithelium are often seen, whereas lymphocytes frequently spill into alveolar spaces. In long-standing lesions, hyaline, collagen, or even amyloid widens the interstitium leading to honeycomb fibrosis. The lymphoid follicles largely consist of cytologically bland B-cells, whereas the interstitial lymphocytes are mostly T-cells. This pattern suggests that the lung can function like a giant lymph node.25 Immunoglobulin heavy chain restriction or gene rearrangement is lacking. In addition to malignant lymphoma, nonspecific interstitial pneumonia (NSIP) and infections including Pneumocystis should be excluded.
Lymphocytic interstitial pneumonia. A. Diffuse alveolar septal expansion with lymphocytes is usually a manifestation of underlying disease. Hematoxylin and eosin, 50× original magnification. B. Benign lymphocytes and plasma cells interfere with gas exchange. The morphologic differential diagnosis includes pneumocystis infection. Hematoxylin and eosin, 60× original magnification.
Given the rarity of LIP, controlled treatment trials have not been undertaken. Corticosteroids are the primary therapy in addition to other immunosuppressive agents, such as cyclophosphamide and chlorambucil, with variable results. One-third of patients have resolution, one-third stabilize, and the remaining third pro-gress.18,54,60 Nonresponders often die of therapy-related infections, but occasional individuals die of end-stage pulmonary fibrosis. Lymphomatous transformation is very unusual; older reports of such most likely represented malignant lymphomas from the start.64
In patients with HIV infections or AIDS, LIP is part of a spectrum of lymphoid proliferations with virtually identical morphologies, but differing clinical presentations. Individuals with so-called diffuse infiltrative lymphocytosis syndrome (DILS) featuring sicca syndrome with increased numbers of circulating CD8+ T-cells in the blood, generalized lymphadenopathy, and enlarged parotid glands, are at high risk of developing LIP.65
LIP is most common is HIV-positive children and is a CDC category B indicator condition in children younger than age 13.66,67 In fact, up to 17% of HIV-positive children have LIP.68 Most present in their second or third year with lung infiltrates, failure to thrive, and increasing respiratory distress. The chest radiograph shows a diffuse micronodular or linear interstitial pattern with hilar and mediastinal widening.69 Therapy is uncertain, response to steroids is unpredictable, and mean survival is 33 months.70
In HIV-positive adults, LIP is quite rare, and tissue sampling is required for diagnosis.57 Most patients present with generalized lymphadenopathy and polyclonal hypergammaglobulinemia. BAL samples feature lymphocytes with CD8+ cells comprising up to 90% of the lymphoid cells.71 Histologically, the lymphoid infiltrates are predominantly T-cells with few plasma cells. Germinal center formation is not a frequent finding. HIV-positive adults with LIP rarely die of the process, but rather of other AIDS-related diseases.
CD, the eponymous term for angiofollicular lymph node hyperplasia, encompasses two clinically and pathologically distinct entities. Solitary lesions usually feature hyaline-vascular (HV-CD) morphology, whereas multicentric disease almost always has a plasma cell pattern (PC-CD).72
Solitary CD is an uncommon form of lymphoid hyperplasia that usually presents as an incidental mediastinal mass in asymptomatic young to middle-aged individuals of either gender.73 Pleural, chest wall, and extrathoracic involvement have been reported, but pulmonary parenchymal disease is a true rarity and most reported cases likely represent nodal rather than true pulmonary disease (Fig. 120-8A).73–78 Solitary HV-CD lesions are usually asymptomatic or rarely cause compression-related symptoms.
Solitary Castleman disease. A. Involved peribronchial lymph nodes are often mistaken for pulmonary parenchymal disease. Airway and vessel distortion may cause symptoms. B. Solitary lymph nodes and rare lung lesions feature hyaline-vascular morphology. Small germinal centers are penetrated by hyalinized venules. The follicle mantle zone rings the burnt-out center in an onionskin pattern. Hematoxylin and eosin, 20× original magnification.
Ninety percent of solitary CDs feature hyaline-vascular morphology, whereas the remainder are the plasma cell variant. HV-CD lymph nodes are enlarged and feature prominent lymphoid follicles with small atrophic germinal centers penetrated by hyalinized venules with plump endothelial cells originating in the interfollicular zone (Fig. 120-8B). Expanded mantle zones have concentric rings of lymphocytes imparting an onionskin appearance. TdT+ T-lymphoblastic populations are increased in this entity.79 The solitary plasma cell variant only involves lymph nodes and has not been reported in the lung. Lymph nodes are hyperplastic with enlarged germinal centers and sheets of interfollicular plasma cells. Clinical suspicion of malignancy typically prompts surgical resection of solitary lesions. Excision results in the disappearance of any symptoms.80 Neoadjuvant anti-CD20 monoclonal antibodies can shrink lesions prior to surgery.81
Multicentric Castleman disease (MCCD) is best considered a virus-driven polyclonal lymphoproliferative process that shares virtually no features with solitary CD.72,82,83 In general, MCCD presents in the fourth and fifth decades of life but earlier in HIV-positive individuals.82,84,85 An increased incidence is noted in the highly active antiretroviral therapy (HAART) era.86 Signs and symptoms include fever, sweating, malaise, anemia, lymphadenopathy, hepatosplenomegaly, ascites, and pleural and pericardial effusions. MCCD appears to be a consequence of infection with human herpesvirus 8 (HHV-8), which in turn promotes production of interleukin-6 (IL-6).72 Laboratory abnormalities include an elevated erythrocyte sedimentation rate, polyclonal hypergammaglobulinemia, and bone marrow plasmacytosis that may lead to pancytopenia.87 A chronic demyelinating polyneuropathy may present as part of POEMS syndrome (Crow–Fukase disease).88 Patients may also develop non-HL. HIV-positive patients with MCCD have a greater likelihood of pulmonary involvement.89
Pulmonary histomorphology correlates with HRCT scan findings of peribronchovascular interstitial thickening and centrilobular nodules (Fig. 120-9A).90,91 Polyclonal peribronchiolar lymphoplasmacytic infiltrates with focal extension into interlobular and alveolar septa may rarely be associated with honeycomb change (Fig. 120-9B). HHV-8 can almost always be demonstrated in lung samples, including BAL, by PCR and in situ hybridization with an HHV-8 probe.92 Although MCCD shares many features with LIP, the plasma cell–rich nature of the infiltrate and presence of HHV-8 discriminate between the two.
Multicentric Castleman disease. A. The bronchocentric nature of this KSHV/HHV8-driven systemic process is apparent at scanning microscopy. Hematoxylin and eosin, 1× original magnification. B. The lymphoplasmacytic infiltrate is confined to the pulmonary interstitium. Honeycomb change may develop. Hematoxylin and eosin, 10× original magnification. (Glass slides used with permission of Dr. J. English, University of British Columbia and Vancouver Hospital, Vancouver, BC.)
Treatment is primarily nonsurgical but survival beyond 5 years is rare.87 Although splenectomy may provide brief relief, chemotherapeutic regimens with or without immunotherapy, including anti–IL-6 and anti-CD20 monoclonal antibodies, appear to induce the longest remissions.74,84,93 An 85% 1-year survival rate is now reported.93
Immunoglobulin G4–related Lung Disease
IgG4-related disease is a recently recognized fibroinflammatory condition with diverse organ manifestations linked by a unique histologic appearance.94 As such, IgG4-related disease mirrors sarcoidosis. Despite a highly variable clinical presentation, the common histologic appearance, elevated serum, and tissue IgG4 levels along with a clinical response to immunosuppression warrant the creation of the broad yet poorly understood entity.95 While most of the initial observations were made in individuals with autoimmune pancreatitis and/or lacrimal and salivary gland disease, the process is now recognized in almost every organ system.96–98 General and organ-specific diagnostic criteria have been developed.95,99 IgG4-related pulmonary disease likely accounts for many fibroinflammatory conditions of unknown etiology including but not limited to inflammatory pseudotumor, interstitial pneumonia, and fibrosing (sclerosing) mediastinitis.26,100 Some patients with autoimmune idiopathic pancreatitis also have lung manifestations.101
Most patients with lung disease are males in their seventh decade of life.102 One half of patients have respiratory symptoms such as cough, exertional dyspnea, hemoptysis, and/or chest pain. Constitutional symptoms are uncommon.103 No risk factors are recognized. Radiographic appearances vary and correlate with histomorphologic findings.104 Solid nodules, bronchovascular, alveolar interstitial, pleural, and airway patterns may be seen, alone or in various combinations.102 The three major histopathologic features are (1) dense lymphoplasmacytic infiltrate, (2) fibrosis, arranged at least focally in a storiform pattern, and (3) obliterative phlebitis (Fig. 120-10).95 IgG4-related pulmonary disease may lack distinct storiform fibrosis while pulmonary arteries, in addition to veins, may be involved.105 Furthermore, vascular changes without vessel lumen obliteration, concentric bronchiolar inflammatory infiltration with germinal centers, and/or prominent eosinophils may be seen.106 Not surprisingly, histomorphologic findings can be considered highly suggestive, probable, or insufficient.95 Unfortunately, the major findings are also seen in a myriad of entities, including but not limited to infections and organizing injuries related to, for example, granulomatosis with polyangiitis (Wegener granulomatosis).107
Immunoglobulin G4–related lung disease. Pulmonary parenchyma is practically overrun with lymphoplasmacytic infiltrates and developing fibrosis. Residual airspaces contain histiocytes. Hematoxylin and eosin, 10× original magnification. (Used with permission of Dr. W. Travis, Memorial Sloan Kettering Cancer Center, New York, NY.)
Tissue and serum IgG4 and IgG levels serve as supplemental data since a diagnosis is based on light microscopic findings. Immunohistochemical stain evaluation requires that one count the three 40x microscopic fields with the highest number of IgG4+ plasma cells and also count the number of IgG+ plasma cells in those same areas. According to the consensus statement, >50 IgG4+ cells per high-power field and >20 IgG4+ cells per high-power field are adequate cutoffs in surgical and nonsurgical lung biopsies, respectively.95 The IgG4+/IgG+ plasma cell ratio should be >40%. However, other lung processes including idiopathic NSIP, usual interstitial pneumonia, connective tissue disease-associated interstitial pneumonias as well as inflammatory myofibroblastic tumor may have increased IgG4+ cell counts.108 Elevated serum IgG4 levels are noted in most patients, although other respiratory, hepatobiliary tract, and connective tissue diseases may be associated with high serum levels.103,109
Standard therapy is not well delineated but most patients respond to glucocorticoids within weeks to months.110,111 Resistant cases may improve with anti-CD20 monoclonal antibody therapy.112 Relapses are common after therapy cessation. An increased risk for non-HL is postulated.113
Malignant Lymphoid Lesions
Within the hematopathology field, past decades will probably be best remembered for the myriad of classification schemes and ever-changing nomenclature. Thankfully, the current WHO classification represents a consensus list of lymphoid neoplasms that appear to be distinct clinical entities.1 Although complex, this scheme is reproducible among trained pathologists. Diagnoses are based on clinical, morphologic, immunophenotypic, and genetic features and not simply on morphologic, immunophenotypic, or even clinical subtleties. B-cell neoplasms, T- and NK-cell neoplasms, and HL are subgrouped according to lineage and stage of differentiation. Within this general context one can understand the practicality of a seemingly cumbersome diagnosis, such as pulmonary extranodal marginal zone B-cell lymphoma of MALT type, given the belief that these lymphomas arise from acquired BALT.
Primary Pulmonary Non-Hodgkin Lymphoma
Although more than half of patients with nodal lymphoma have lung involvement, primary pulmonary lymphomas comprise less than 0.5% of primary lung neoplasms.114,115 Furthermore, the most common primary lung lymphoma, marginal zone non-HL of MALT origin, represents less than 10% of extranodal lymphomas.116 Non-HLs are considered lung primaries when the lung is the major site of disease at the time of diagnosis.117,118 Thus, up to 20% of these lung lymphomas involve hilar and/or mediastinal lymph nodes. Pulmonary lymphomas have a range of morphologies and clinical aggressiveness such that separating the tumors into low- and high-grade categories is a dangerous oversimplification. Although most lung non-HLs differ from nodal lymphomas and are thought to have their origin in BALT, traditional nodal non-HLs, such as follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, and CD30+ anaplastic large cell lymphoma, also present as pulmonary primaries (Table 120-2).19,119–122
Table 120-2Lymphoid Neoplasms Commonly Involving the Lungs ||Download (.pdf) Table 120-2Lymphoid Neoplasms Commonly Involving the Lungs
|B-cell neoplasms |
|T-cell and NK-cell neoplasms |
|Hodgkin lymphoma |
Extranodal Marginal Zone B-Cell Lymphoma of MALT Type
Recent recognition that most primary pulmonary lymphomas arise from BALT revolutionized our thinking about extranodal lymphoid lesions. This hypothesis suggests that some degree of lymphoid hyperplasia is a necessary precondition for the development of these lymphomas and explains the association with inflammatory and autoimmune processes as well as the common finding of reactive germinal centers in lymphomas of BALT. These relatively indolent lymphomas must be discerned from both reactive processes, including NLH and LIP as well as more aggressive lymphomas.
Patients tend to be in their fifth through seventh decades of life with a slight male preponderance.23,123 Those younger, including children, almost always have pre-existing immunosuppression such as HIV infection.19 Most individuals are asymptomatic and are noted to have an abnormality on a routine chest radiograph. The presence of dyspnea, cough, hemoptysis, and shortness of breath reflect extensive disease causing airway constriction, poor compliance, and atelectasis. “B” symptoms are rare.119 Mean lymphocyte counts are typically normal and peripheral blood does not show a leukemic phase, whereas a monoclonal gammopathy, usually IgM, is noted in up to 30% of patients.124
Chest radiographs and HRCT scans show either peripheral or perihilar solitary or multiple masses or alveolar opacities with air bronchograms.125,126 Cavitation, calcification, and pleural effusions are very rare, and hilar adenopathy is present in less than 25% of cases.24 The interval between the finding of a radiologic abnormality and definitive pathologic diagnosis averages over 5 years, reflecting the tendency of this tumor to remain localized for a long period.23,123 Thus, it is not surprising that up to 80% of individuals present with stage I disease.19,117,118,120
Grossly, nodular areas vary from 2.0 to 20 cm and are tan and fleshy. Underlying lung architecture may be preserved (Fig. 120-11A). At low magnification these lymphomas appear as diffuse infiltrates surrounding reactive follicles with peripheral tracking along bronchovascular bundles and interlobular septa (Fig. 120-11B,C). Invasion of bronchial cartilage and visceral pleura are common. At high magnification, the small lymphoid cells may have round nuclei with little cytoplasm (centrocyte-like) or irregular nuclear contours and abundant clear cytoplasm (monocytoid differentiation) (Fig. 120-11D). Plasmacytic differentiation is also common. Scattered larger cells (immunoblasts) can also be seen. Malignant cells often infiltrate reactive germinal centers (follicular colonization) as well as bronchial, bronchiolar, and alveolar epithelium (lymphoepithelial lesions). This latter finding is seen in up to 90% of cases, but is not a useful diagnostic criterion.122,124 Secondary features include fibrosis, sclerosis, and amyloid and sarcoidal granulomas.37,38 Involved mediastinal lymph nodes feature typical morphology of nodal marginal zone B-cell non-HL.
Extranodal marginal zone B-cell lymphoma of MALT type. A. Tan fleshy tumor fills alveolar spaces but preserves lobular architecture. B. Malignant lymphoid cells overrun lung tissue. Germinal centers are usually prominent. Hematoxylin and eosin, 4× original magnification. C. Malignant lymphoma often tracks along lymphatic pathways beyond the dominant mass lesion. If such a region was sampled the differential diagnosis would include diffuse lymphoid hyperplasia. Involvement of visceral pleura suggests the malignant nature of the process. Hematoxylin and eosin, 4× original magnification. D. Most pulmonary marginal zone B-cell lymphomas of MALT type are composed of small monotonous round (centrocyte-like) B-lymphocytes. Hematoxylin and eosin, 40× original magnification.
When light microscopic features favor a diagnosis of this lymphoma, all available ancillary studies should be utilized to make a definitive diagnosis. The neoplastic cells are monoclonal B-cells, which may be identified with CD20 or CD79a stains.122,123 Light chain restriction is present in all cases with equal κ and λ percentages; however, PCR amplification of the immunoglobulin heavy chain gene from paraffin sections detects monoclonality in only 60% of tumors.127 Fifty percent to 60% of marginal zone B-cell lymphoma of MALT type demonstrate t(11;18), whereas t(1;14) or trisomy 3 may also occur.128–130
The differential diagnosis includes NLH, LIP as well as pulmonary involvement with a variety of different malignant lymphomas, such as lymphoplasmacytoid lymphoma/immunocytoma. These distinctions are of paramount importance and the surgical pathologist or hematopathologist has the necessary tools to make a correct diagnosis.
Pulmonary marginal zone B-cell lymphomas of MALT are indolent tumors with 85% to 95% 5- and 10-year survival rates.23,117,118,123,131 In several studies, median survival was not reached at 10 years. Thus, patients with resectable disease are treated with resection, but those with diffuse lung involvement may be followed and treated with chemotherapy with or without anti-CD20 antibodies.119,131 Patients with systemic symptoms at presentation may have a worse prognosis. Lymphoma recurs in the lungs or in other MALT sites such as salivary gland, orbital, or gastrointestinal tract in almost half of patients, and up to 15% of patients experience transformation of their lymphomas into more aggressive and usually deadly forms including diffuse large B-cell non-Hodgkin lymphoma (DLBCL).23,124
Other Non-Hodgkin Lymphomas
Non-HLs other than extranodal marginal zone B-cell lymphomas originating in the lung are very rare and comprise less than one-fourth of primary lung lymphomas.23,120,122,124,132 These tumors represent a heterogeneous group consisting primarily of DLBCL with fewer cases of follicular lymphoma, and rare examples of mantle cell lymphoma, lymphoplasmacytic lymphoma/immunocytoma, Burkitt lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphomas.132–136 Rare AIDS-related primary pulmonary B- and T-cell lymphomas containing EBV RNA are also described.137,138 Of note, only primary pulmonary DLBCL appears to arise from BALT and is also weakly associated with both fibrosing interstitial lung diseases and connective tissue diseases.120,123
Although each lymphoma subtype has particular morphologic features, primary pulmonary DLBCL is best characterized clinically.120,122–124 Patients are usually adults but younger individuals with immunodeficiency states may be affected.114,119,124 Unlike those with extranodal marginal zone B-cell lymphomas of MALT, most patients present with shortness of breath, fever, chest pain, and hemoptysis and frequently develop extrapulmonary lesions and paraneoplastic syndromes shortly after diagnosis. Restrictive physiology is often observed. Imaging studies reveal solitary or multifocal nodules or infiltrates measuring at least 3.0 cm.123 Cavitation and pleural effusions are frequently seen and regional lymph nodes are involved in up to 50% of cases.
Resected lesions are white-tan and fleshy with areas of necrosis. Histologically, largely necrotic nodules or striking lymphangitic growth with parenchymal destruction are accompanied by inflammatory infiltrates. Infarction is not uncommon. Sheets of malignant mitotically active B-cells are two to four times the size of normal lymphocytes (Fig. 120-12). Vascular infiltration and pleural involvement are common features and airway destruction leads to postobstructive pneumonia. Residual BALT hyperplasia and low-grade marginal zone lymphoma may be seen at the periphery of the mass. Neoplastic cells express pan-B antigens CD20 and CD79a. Monotypic immunoglobulin light chain expression can be demonstrated.139 Although the cytologic atypia and necrosis in these lymphomas make it easy to distinguish them from benign lymphoid processes and extranodal marginal zone lymphomas, confusion with poorly differentiated carcinomas or HL can occur.
Diffuse large B-cell lymphoma. This lymphoma is composed of large cells with irregular nuclear features and significant mitotic activity. The B-cell phenotype is demonstrated by flow cytometry or immunohistochemistry. This lymphoma not only looks more aggressive than marginal zone B-cell lymphoma of MALT type, but also follows an aggressive clinical course. Hematoxylin and eosin, 40× original magnification.
Localized DLBCL is potentially curable with surgery and adriamycin-based chemotherapy, but 5-year survival rates do not surpass 60% and the median survival is only 3 years.19,114,119 Only half of HIV-positive patients achieve clinical remission and those remissions usually last only 6 months.
Lymphomatoid granulomatosis (LYG) is one of the most confusing lesions in all of human disease. The original investigators were not certain whether this lung-based process, which also involves the central nervous system, skin, and other organs, was a malignant lymphoma or a variant of granulomatosis with polyangiitis (Wegener granulomatosis).140 Since that time erroneous ideas concerning its etiology and histogenesis have muddled the entity even further. We now recognize LYG as an EBV-driven B-cell lymphoproliferative disorder arising in individuals with either obvious or clinically undetected defects in cell-mediated and perhaps also humoral immunity.1,141–144 In many ways, LYG is similar to posttransplant lymphoproliferative disorder (PTLD) with a spectrum of clinical behaviors.
Although quite rare, LYG has characteristic clinical features.145,146 Patients usually present in the fifth or sixth decades of life but children and the elderly can be stricken. Men are affected two to three times as often as women. Dyspnea, cough, chest pain along with fever, and malaise and weight loss are the most common presenting complaints and up to 40% of patients also have skin nodules, ulcers, rashes, peripheral neuropathies, or symptoms referable to central nervous system involvement. Gastrointestinal, musculoskeletal, or nodal involvement is uncommon. Presentation as an asymptomatic solitary lung nodule is very rare.
Laboratory findings can include either leukocytosis or leukopenia and elevated serum IgG or IgM.145 Cerebrospinal fluid may have abnormal protein and glucose levels. Serologies for autoimmune diseases are negative but evidence of EBV infection has been reported.
Chest imaging in up to 70% of patients reveals bilateral middle and lower zone lung nodules as large as 10 cm.140,145,147 Coalescence and cavitation are often seen. Nonspecific reticulonodular infiltrates as well as solitary infiltrates or masses are less common findings. Pleural effusion is present in up to one-third of patients.
Macroscopically the lungs and other affected organs contain yellow-white well-demarcated masses with either solid or granular textures (Fig. 120-13A). Microscopically LYG is composed of nodular lymphoid infiltrates centered on lymphatic routes including bronchovascular bundles. As the lesions increase in size, blood vessels are encircled, infiltrated, and perhaps occluded but not obliterated by the process (Fig. 120-13B). The infiltrate and nodules are composed of a heterogeneous population of small, intermediate, and large lymphocytes (Fig. 120-13C). The large cells are in the minority but can be very atypical or pleomorphic, stain as B-cells (CD20+ and CD79a+) and are EBV-infected according to PCR and in situ hybridization studies. CD30 positivity is also noted in infected monoclonal cells. The smaller and more numerous cells stain as T-cells (CD3+, CD4+, and/or CD8+). Secondary features include interstitial and consolidative pneumonia. Despite its designation, granulomas are not seen.
Lymphomatoid granulomatosis. A. Most lesions are well circumscribed with central necrosis. However, this macroscopic appearance is not pathognomonic for LYG. B. Lung parenchyma often features irregular areas of necrosis with preserved vessels. Hematoxylin and eosin, 4× original magnification. C. The lymphoid infiltrate expands a vessel wall. Morphology does not suggest lymphoma yet cytologic atypia is noted. This grade 2 lesion was treated with combination chemotherapy but clinical remission was not achieved. Hematoxylin and eosin, 60× original magnification.
The grading system for LYG is based on the number of atypical large EBV-infected cells (Table 120-3). Grade 1 lesions probably include cases of so-called benign lymphocytic angiitis and granulomatosis, whereas grade 3 proliferations are alternatively considered a subtype of diffuse large cell lymphoma (DLCL). With greater relative numbers of EBV-infected cells, one observes more necrosis and a more aggressive clinical course.1 Given the complex histologic features of LYG and need to identify scattered large cells in an inflammatory mass, diagnosis and accurate grading almost always requires a surgical lung biopsy.
Table 120-3Histologic and In Situ Hybridization Grading of Lymphomatoid Granulomatosis ||Download (.pdf) Table 120-3Histologic and In Situ Hybridization Grading of Lymphomatoid Granulomatosis
|Grade 1 |
|Grade 2 |
Angiocentric, predominantly polymorphous, infiltrate with occasional large or atypical lymphoid cells and parenchymal necrosis
Scattered EBV-infected cells (5–20 per high-power [40×] field)
|Grade 3 |
Although similar to T-cell–rich B-cell lymphomas such as angiocentric nasal NK/T-cell lymphoma and PTLD, the former entity lacks EBV-infected monoclonal B-cells and the latter lacks the angiocentricity of LYG. Other diagnostic considerations include HL and necrotizing inflammatory conditions.
The natural history is variable and clinical behavior ranges from indolent to aggressive.148 Spontaneous remissions and therapy-induced remissions occur but more than 60% of patients die, with a median survival of 14 months.145 Although most organ systems can be involved, lymphoid tissue including the spleen is only involved in 25% of patients who develop grade 3 lesions. Hemophagocytic syndrome is related to systemic EBV infection rather than bone marrow involvement. Histologic grade correlates with outcome. Most patients have either grade 1 or 2 disease; one-third of those with grade 1 lesions progress to grade 3/malignant lymphoma, whereas two-third of those with grade 2 lesions develop grade 3/malignant lymphoma. Asymptomatic patients or those with minimal disease and grade 1 or 2 histology may be observed; those with symptomatic grade 1 or 2 histology require treatment with corticosteroids or single or multiagent chemotherapy. Clinically aggressive grade 1 and 2 and all grade 3 lesions are treated as DLCL with combination chemotherapy.148 Therapies targeting EBV-bearing B-cells (interferon-α2β) or reactive T-cells (i.e., cyclosporine) as well as stem cell transplantation, have been reported.148,149
Intravascular large B-cell lymphoma
Intravascular large B-cell lymphoma (IVLBCL) is a rare non-HL characterized by lymphoma cells only in the lumina of small vessels, particularly capillaries.1,150 A Western variant manifests with symptoms related to the involved organ, while an Asian variant presents with multiorgan failure, hepatosplenomegaly, pancytopenia, and hemophagocytic syndrome.151,152 Although patients with the Western variant most often present with neurologic or dermatologic manifestations, older patients may complain of fever, dyspnea, cough, chest pain, or present with respiratory failure.153–156 Hypoxia and decreased diffusion capacity are seen. Chest radiographs demonstrate reticulonodular infiltrates, whereas CT scans can show patchy ground-glass opacities.153,154,157
Low magnification histology demonstrates a diffuse interstitial process resembling cellular interstitial pneumonia yet higher magnification reveals large cells with prominent nucleoli confined to arteries, veins, lymphatics, and especially capillaries (Fig. 120-14). Fibrin thrombi may be noted.
Intravascular large B-cell lymphoma. Malignant lymphoid cells remain confined to vascular channels (arrowheads). Hematoxylin and eosin, 60× original magnification.
Although all cases of IVLBCL are B-cell lymphoma (CD19+, CD20+, CD79a+), a T-cell phenotype associated with EBV has been described and should be considered a different entity.158–160 Although the intravascular nature of the lymphoma is not understood, absence of adhesion molecules CD54 (I-CAM-1) and CD29 (β1 integrin) may prevent neoplastic cell–endothelial cell interactions and extravascular spread.161
Half of cases are diagnosed at autopsy yet a diagnosis is possible on thoracoscopic and even transbronchial biopsies.155,162,163 Immunohistochemical stains are necessary to discern IVLBCL from metastatic carcinoma, malignant melanoma, and leukemia. Although prognosis is poor, complete remission and long-term survival can be achieved with prompt diagnosis and aggressive combination chemotherapy and perhaps anti-CD20 monoclonal antibodies.160,164
Primary pulmonary HL is very rare.165 This is in part due to the requirement that, unlike non-HL, regional lymph nodes be free of disease to qualify as a lung primary.
Primary pulmonary HL shows the usual bimodal age distribution of systemic HL but patients are slightly older.166–168 Women outnumber men by 1.5 to 1. Symptoms include cough, dyspnea, hemoptysis, and chest pain and one-third of patients experience B symptoms.166 Radiographs demonstrate reticulonodular and linear infiltrates or multiple nodular lesions. Solitary lesions and consolidation are also seen. Upper lobe disease is most common, and atelectasis and cavitation are frequently observed.169
Tumors have a multinodular white firm macroscopic appearance and histologically grow along lymphatic routes in the lung. When small nodules coalesce, central necrosis is apparent. Visceral pleura is often infiltrated while bronchial involvement can result in plaque-like nodules, polypoid endobronchial masses, or airway collapse.170,171 Within the WHO histologic classification of HL, one cannot be certain if nodular lymphocyte–predominant HL and the four subtypes of classical HL all involve the lung. Nodular sclerosis and mixed cellularity subtypes of HL are more commonly seen than lymphocyte rich, whereas lymphocyte depleted has not been reported in primary pulmonary HL.166,167 Diagnosis requires the identification of Reed–Sternberg cells or variants (usually CD15+ or CD30+) within the appropriate inflammatory background. Central necrosis, granulomatous inflammation, and vascular permeation by the polymorphous infiltrate are commonly seen.
The morphologic differential diagnosis includes inflammatory and malignant processes. Infections, granulomatosis with polyangiitis (Wegener granulomatosis), and sarcoidosis as well as poorly differentiated carcinomas, LYG, and a variety of non-HLs must be considered. The nonneoplastic entities can be discerned histologically, whereas the neoplasms require at least immunohistochemical studies.
The prognosis for patients with primary pulmonary HL is variable.168 Individuals with all types and stages of primary pulmonary HL have a 5-year survival of almost 75%.166,167 Relapses occur in the lung and elsewhere and appear associated with multiple lobe involvement, pleural invasion, cavitation, and presence of B symptoms.
Secondary Lymphoma Involving the Lung
Secondary lung involvement with nodal and extranodal lymphomas is significantly more common than primary pulmonary lymphoma. Lung involvement with common nodal and disseminated lymphomas surpasses 50% during life and at autopsy.165,172–174 Clinical and radiologic features may suggest an infectious process, but tissue samples demonstrate a lymphangitic pattern of disease (Fig. 120-15A). Patchy infiltrates and endobronchial masses are, however, not uncommon.175
Lung involvement with Hodgkin lymphoma. A. The striking lymphangitic distribution of this dense white tumor indicates secondary pulmonary involvement. B. A uninucleate Reed–Sternberg cell with typical prominent nucleolus (center) is surrounded by lymphocytes and eosinophils. Hematoxylin and eosin, 60× original magnification.
Morphology does not usually allow for distinction between primary and secondary lung disease. For example, pulmonary involvement with nodal marginal zone lymphoma is indistinguishable from primary pulmonary extranodal B-cell lymphoma of MALT. Thus, clinical history and review of previous diagnostic material are necessary for proper diagnosis. Secondary lymphomas involving the lung can also transform to more aggressive histology with increased numbers of large cells. This phenomenon is not infrequently seen in samples from patients with CLL/SLL.
Several particular systemic lymphoproliferative disorders that may present with significant lung pathology warrant additional discussion. Mycosis fungoides may involve the lung after dissemination of cutaneous disease or as part of the Sézary syndrome. Indeed, the lung is the second most common extracutaneous site after lymph nodes.176,177 Clinical and radiographic features often mimic pneumonia or even acute respiratory distress syndrome with nodular and diffuse disease.178 Tissue samples demonstrate air space and interstitial infiltrates along lymphatic routes in addition to occasional granulomas, extensive vascular infiltration, and necrosis. Cells range from small with irregular twisted nuclei to large with prominent nucleoli.
The lungs are also frequently involved with angioimmunoblastic T-cell lymphoma.179 Although originally described as a reactive process (angioimmunoblastic lymphadenopathy with dysproteinemia), this malignant disease in the lung can be mistaken for interstitial pneumonia.180–182 However, the lymphatic distribution of atypical “clear” cells with indented nuclei admixed with immunoblasts, plasma cells, and histiocytes is neoplastic and must be distinguished from HL. Pulmonary involvement with HL is recognized at presentation in more than 10% of patients with mediastinal or extrathoracic disease. Fifty percent of patients with HL have relapses in the lung and almost 60% are noted to have pulmonary involvement at autopsy.165,183 Unlike primary pulmonary HL, secondary involvement rarely manifests with large nodules, whereas infiltrates often surround blood vessels and may feature greater numbers of atypical cells and fewer inflammatory cells than in primary HL (Fig. 120-15B).184
Extraosseous plasmacytomas most often affect the upper respiratory tract. Primary plasmacytomas of the lung are exceedingly rare; patients are usually in their fifth and sixth decades of life and asymptomatic.44,185,186 Cough, dyspnea, and hemoptysis have been reported. Unlike multiple myeloma, individuals may lack a serum M-protein or Bence Jones light chains in the urine. Radiographs most commonly demonstrate a midlung or hilar solitary mass, but peripheral lesions amenable to transthoracic-needle aspiration biopsy occur.187–189
Tumors range from 2.5 to 8.0 cm and most often involve a major bronchus with occasional involvement of regional lymph nodes. Histologically, sheets of plasma cells including binucleate forms overrun lung parenchyma and bronchial cartilage (Fig. 120-16). Fibrous bands course through the tumor and amyloid or light chain may be associated with the neoplasm. κ and λ light chains as well as IgG, IgA, and IgD can be expressed immunohistochemically or produced as M-proteins by the tumor.185,190,191 The pathologist must discriminate between plasmacytoma and marginal zone lymphoma with plasmacytoid features as well as inflammatory myofibroblastic tumor.
Plasmacytoma of lung. Sheets of plasma cells usually form a solitary nodule. Cytologic atypia is often seen. Since this lesion is less common than pulmonary involvement with multiple myeloma, clinical correlation is always required. Hematoxylin and eosin, 40× original magnification.
Although the natural history of this rare tumor is not well delineated, it appears that cases are either cured with either surgical excision or radiation therapy, or evolve into multiple myeloma.185,192,193 The presence or absence and amount of M-protein may mirror tumor burden and clinical course while an increase or decrease in levels may be associated with recurrence or successful treatment, respectively. An overall 5-year survival of 40% has been reported.185,194
Pulmonary involvement with multiple myeloma is more common than pulmonary plasmacytoma.40,195,196 Lung involvement may be nodular or have a diffuse lymphangitic pattern.197 Nodular or diffuse amyloid deposition may accompany the neoplastic cells. Intracytoplasmic crystalline casts similar to those seen in the kidney are occasionally observed.198
Posttransplant Lymphoproliferative Disorder
Posttransplant lymphoproliferative disorder (PTLD) is a lymphoid proliferation or lymphoma that develops as a consequence of immunosuppression in solid organ or bone marrow allograft recipients. Eighty percent of cases are associated with EBV infection in the setting of decreased T-cell immune surveillance; the etiology of EBV-negative PTLD is unknown.1,184 Most cases are of host origin while approximately 10% of cases are of donor origin.1 Those of donor origin are more common in lung and heart–lung transplantation patients due to the presence of donor BALT in the lungs.199–203
Allograft and extranodal MALT sites including Waldeyer ring, lung, and gastrointestinal tract, are usually involved and incidence varies based on type of allograft and immunosuppression regimen. One percent of renal transplant patients but up to 10% of lung transplant recipients are stricken.202
The majority of cases of PTLD in lung transplant recipients and approximately 10% of cases in other solid organ transplant recipients manifest with pulmonary lesions. Individuals may be asymptomatic or present with constitutional symptoms. In lung transplant patients, respiratory failure may occasionally occur. Radiographs demonstrate nodular or diffuse reticulonodular infiltrates, solitary nodules, or multiple mass lesions with or without regional lymphadenopathy.204
Morphologic categories of PTLD include early lesions, polymorphic PTLD, monomorphic PTLD, HL, and HL-like PTLD (Table 120-4). Most proliferations are B-cell processes, although T-cell lesions are seen.205 Early lesions usually involve lymph nodes and Waldeyer ring rather than lung; lymphoid tissue is hyperplastic with either sheets of plasma cells or paracortical expansion with immunoblasts that resemble infectious mononucleosis morphology. Polymorphic and polyclonal proliferations feature mixtures of small lymphocytes, plasma cells, and immunoblasts and may progress to monomorphic monoclonal proliferations with sheets of large transformed cells resembling aggressive lymphoma (Fig. 120-17A,B). In fact, the monomorphic monoclonal proliferations are subclassified according to lymphoma classification.1 HL and HL-like PTLD are very rare and purportedly similar to methotrexate-related HL.206 The morphologic findings may be difficult to differentiate from allograft rejection; immunophenotyping is essential, whereas molecular genetic testing for clonality and in situ hybridization studies for EBV may be necessary. For these reasons, tissue procurement rather than fine-needle aspiration biopsy is preferred for diagnosis.
Posttransplant lymphoproliferative disorder. A. This polymorphic lesion features small and large lymphocytes admixed with plasma cells. Hematoxylin and eosin, 60× original magnification. B. Monomorphic lesions often comprise large atypical cells with numerous mitoses. According to the WHO scheme this lesion is classified as a diffuse large B-cell lymphoma. Hematoxylin and eosin, 60× original magnification.
Table 120-4Posttransplant Lymphoproliferative Disorders ||Download (.pdf) Table 120-4Posttransplant Lymphoproliferative Disorders
|Early lesions |
|Polymorphic PTLD |
|Monomorphic PTLD |
Diffuse large B-cell lymphoma
Plasma cell myeloma
|T-cell neoplasms |
|Hodgkin lymphoma and Hodgkin lymphoma-like PTLD |
Treatment often starts with reductions in immunosuppression, though this runs the risk of losing the allograft.207 Early lesions usually regress while only a proportion of polymorphic and monomorphic PTLD respond.208 Neither morphology nor molecular characterization of the PTLD can predict response to reduction in immunosuppression. Nonresponders, or those with bulky or multisystem disease are treated with anti-CD20 antibody therapy (rituximab).209 Cytotoxic chemotherapy and perhaps radiation therapy are reserved for refractory cases and those who are CD20 negative. Early diagnosis with prompt reduction of immunosuppression and/or anti-CD20 antibody therapy has improved the prognosis of patients with PTLD.210,211
Leukemic Infiltrates Involving the Lung
Secondary effects of leukemia or therapy including infections, alveolar proteinosis, leukemic cell lysis pneumopathy, hemorrhage, and chemotherapy toxicity afflict many leukemia patients but significant direct lung involvement with leukemia affects less than 10% of individuals.212,213 Leukemic lung infiltration is often found at autopsy or as an “incidental” finding in a tissue sample demonstrating an infectious process, and only causes symptoms in those patients with high (40% or greater) blast counts.214 Cough, dyspnea, and hemoptysis may precede the leukemia diagnosis for months or develop suddenly.215 Bronchiolar involvement producing asthma-like symptoms has been reported. Radiographic findings run the gamut from localized to diffuse infiltrates.216–218
All leukemia subtypes can involve the lung but acute myeloid leukemia, acute lymphoblastic leukemia, and CLL/SLL are most often seen.219 Infiltrates are predominantly restricted to the pulmonary lymphatic distribution and rarely form micronodules (Fig. 120-18). Bronchiolocentricity may be mistaken for bronchiolitis. Infiltrates can be subtle and chloroacetate esterase and myeloperoxidase stains may be useful in diagnosis and subtyping. Leukemic counts greater than 200,000/μm cause capillary leukostasis with resultant thrombosis. Pulmonary edema, infarct, and diffuse alveolar damage may result.
Leukemic infiltrate in the lung. Primitive mononuclear cells with clumped chromatin (blasts) expand alveolar septa and spill into air spaces. Although an infectious process was suspected clinically, acute myeloid leukemia represented the only lung pathology. Hematoxylin and eosin, 60× original magnification.
Patients with agnogenic myeloid metaplasia (myelofibrosis) occasionally have pulmonary manifestations.220–223 Diffuse and nodular foci of extramedullary hematopoiesis usually follow lymphatic routes and associated fibrous tissue can form large nodules. Interstitial fibrosis often results and may be mistaken for a primary chronic fibrosing interstitial pneumonia.224
In addition to acute complications of leukemia, patients undergoing bone marrow transplantation for leukemia may experience a variety of pulmonary complications including pulmonary edema, diffuse alveolar damage/acute respiratory distress syndrome, bacterial, fungal, and viral infections and GVH disease.214 Acute GVH rarely involves the lung but lymphocytic bronchiolitis, LIP, constrictive bronchiolitis, and pulmonary fibrosis are all considered within the spectrum of chronic pulmonary GVH. However, these manifestations may also represent cytotoxic chemotherapeutic effect.
Disseminated lymphomas frequently affect the visceral pleura and pleural cavity. Non-HLs often invade the visceral pleura while HL often causes pleural effusions due to mediastinal lymph node involvement and secondary lymphatic obstruction. Leukemia and multiple myeloma infrequently manifest with pleural involvement.225 Diagnosis often can be established with effusion cytology and flow cytometry; parietal pleural biopsies are rarely required.
Primary pleural lymphomas are much less common and only two types have been described: Primary effusion lymphoma (PEL) and pyothorax-associated lymphoma (PAL). Both are associated with EBV but similarities end there.
Primary Effusion Lymphoma
Primary effusion lymphoma (PEL) is a rare large B-cell lymphoma that presents as either a pleural, pericardial, or peritoneal cavity effusion without a detectable tumor mass.226 All cases are associated with Kaposi sarcoma–associated herpesvirus/Human herpes virus-8 (KSHV/HHV8) and most occur in young to middle-aged HIV-positive homosexual males.227 Rare cases have been reported in supposedly immunocompetent elderly individuals and HIV-negative cardiac transplant patients.228 A solid tissue-based variant is also recognized.229 Some patients have pre-existing Kaposi sarcoma and rare cases are associated with MCCD.230 In addition, most cases are coinfected with EBV but a pathogenetic role for this virus has not been elucidated.231,232
Effusion cytology specimens demonstrate large lymphoid cells with large round to irregular nuclei and frequent multinucleation as well as numerous mitotic figures (Fig. 120-19). Plasma cell features may be prominent and anaplastic cells can be seen. Pleural biopsies feature tumor cells admixed with fibrin. Chest wall or lung invasion are very rare findings. B-cell lineage is confirmed by immunoglobulin gene rearrangement studies but neoplastic cells rarely express B-cell markers. CD45, CD30, and plasma cell markers CD38 and CD138 are expressed. These findings suggest a postgerminal center B-cell origin. Rare cases with T-cell lineage have been reported.233
Primary effusion lymphoma. This pleural cytology demonstrates a large cluster of pleomorphic cells. This KSHV/HHV8-associated lymphoma is of B-cell origin despite the absence of immunohistochemical staining for B-cell markers. Modified Wright–Giemsa, 60× original magnification.
This lymphoma is extremely aggressive with survival measured in months. Combined antiviral therapy and chemotherapy are offered.234,235
Pyothorax-associated lymphoma (PAL) develops in the pleural cavities of immunocompetent patients with chronic suppurative pleuritis. Most cases arise decades after artificial pneumothorax for treatment of tuberculosis or pleuritis secondary to pulmonary asbestosis.236 Approximately 2% of individuals with chronic pyothorax develop PAL. EBV is strongly associated but the pathogenesis is not clearly understood.237 It is postulated that immunocompetent cells cannot enter the diseased pleural cavity resulting in local immunodepression facilitating proliferation of EBV-infected lymphocytes.
Patients, more often males, are usually in their sixth to eighth decades of life and usually present with chest pain, back pain, or shoulder pain and dyspnea.236 Radiographic studies demonstrate an intense 18F fluorodeoxyglucose positron emission tomography–positive visceral or parietal pleural mass invading chest wall, lung, pericardium, or diaphragm in the setting of pleural fibrosis and calcification.238,239 In contrast to PEL, pleural effusion is not seen. Solid organ involvement is rare.237
Biopsy and resection specimens show masses composed of sheets of large atypical lymphoid cells with prominent nucleoli and basophilic cytoplasm (Fig. 120-20). Mitotic figures and apoptotic bodies as well as necrosis abound. Immunohistochemical studies discern this high-grade lymphoma from PEL. Typically lymphoma cells associated with PAL stain for B-cell antigens CD20 and CD79a, plasma cell markers CD38 and CD138, and on occasion a T-cell marker such as CD2, CD3, CD4, or CD7.1,240 Immunohistochemistry is positive for EBV, whereas KSHV/HHV8 is absent.241,242
Pyothorax-associated lymphoma. Unlike primary effusion lymphoma, this aggressive large-cell B-cell lymphoma is pathogenetically linked to EBV and forms a mass lesion. Hematoxylin and eosin, 60× original magnification.
The prognosis for patients with PAL is dismal with most deaths occurring within 1 year. However, combination chemotherapy and radiotherapy may prolong survival with 5-year survival rates of 20%.236
Pulmonary and pleural lymphomas and reactive processes are uncommon entities with rich historical contexts. Current immunohistochemical and molecular methods allow for accurate reproducible classification. Since most lesions arise from BALT, using this construct to order most lung lymphoid proliferations is very appealing. The wide variety of diseases associated with underlying immunologic disorders is only surpassed by the complexities of the primary lymphoproliferative disorders themselves. Clinicopathologic correlation is required for interpretation of virtually all these lesions. Sound diagnoses combined with improved therapies will hopefully improve patient quality of life and survival.
et al eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2008.
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