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Update on nonneoplastic pulmonary lymphoproliferative disorders and related entities.

Recent discoveries have expanded the spectrum of nonneoplastic pulmonary lymphoproliferative disorders and have provided new insights into their pathogenesis and treatment. This article will review the thoracic manifestations of immunoglobulin (Ig) G4-related sclerosing disease and summarize the concepts of follicular bronchiolitis, lymphocytic interstitial pneumonitis (LIP), and nodular lymphoid hyperplasia.


IgG4-related sclerosing disease encompasses a spectrum of fibroinflammatory lesions that affect various organ systems including the pancreas, bile duct, gallbladder, retroperitoneum, salivary gland, aorta, lacrimal gland, kidney, mediastinum, and lung. Manifestations in these organs consist of tumorlike masses and/or fibrosis associated with infiltration by numerous IgG4-positive plasma cells and lymphocytes. Affected patients often have high levels of serum IgG4. Histologic features were initially described in cases of autoimmune pancreatitis and include (1) dense fibrosis with an associated mixed inflammatory infiltrate with IgG4-positive plasma cells, (2) infiltration or granulomas in some cases, and (3) obliterative phlebitis. Subsequent reports (1-4) have shown similar features at sites of extrapancreatic involvement. Diagnosis of IgG4-related sclerosing disease is important to avoid unnecessary surgery from a misdiagnosis of malignancy. In addition, the lesions often respond readily to steroid therapy. (2)

While IgG4-related sclerosing disease was initially reported in the context of autoimmune pancreatitis, recent reports have shown that pulmonary involvement may occur in association with, or sometimes independently from, autoimmune pancreatitis. (5-8) Reported pulmonary manifestations of IgG4-related sclerosing disease have included fibroinflammatory masses, the plasma cell-rich variant of inflammatory pseudotumor, an interstitial pneumonitis resembling idiopathic nonspecific interstitial pneumonia (NSIP), (7) and some lesions formerly thought to represent grade I lymphomatoid granulomatosis. (8) Some cases of sclerosing mediastinitis, which may secondarily affect the lung, have also been reported as a manifestation of IgG4 systemic sclerosing disease. (9,10) While summarized below (Table 1), these reports are recent and include relatively few patients. Accordingly, additional studies will be needed to confirm the significance of these findings. The overlap in clinical, morphologic, and immunohistochemical features between these entities suggest that they represent different morphologic manifestations of the same clinicopathologic entity.

Fibroinflammatory Masses

A recent poster and subsequent article by Shrestha et al (6) at the 2009 United States and Canadian Academy of Pathology meeting in Boston, Massachusetts, compared histologic and immunohistochemical features in biopsy specimens from a series of 18 patients with IgG4-associated fibroinflammatory pulmonary lesions to those in biopsy specimens from patients with pulmonary involvement by a variety of other conditions including Erdheim-Chester disease (3 patients), Sjogren syndrome (19 patients), inflammatory pseudotumor (10 patients), and various other interstitial and inflammatory diseases (61 patients). Their 18 cases of IgG4-associated fibroin-flammatory lesions included 6 patients with known autoimmune pancreatitis. They found that the pulmonary lesions had characteristic morphology. Biopsy samples generally showed a plasma cell-rich lymphohistiocytic infiltrate with fibrosis in a lymphangitic distribution, increased numbers of IgG4-positive plasma cells on immunohistochemistry (range, 20-231 in 3 high-power fields), an increased IgG4 to IgG plasma cell ratio (range, 10%-72%), and involvement of both arteries and veins by intimal endothelial inflammation (Figure 1, a through g). Additional features included fibrinous pleuritis and occasional histiocytes with emperipolesis of lymphocytes and associated lymphatic dilatation. (6) In contrast to the above cases, biopsy specimens of patients with pulmonary involvement by Sjogren syndrome or Erdheim-Chester disease did not show increased numbers of IgG4-positive plasma cells. (6)

Plasma Cell-Rich Variant of Inflammatory Pseudotumor

Inflammatory pseudotumors refer to a fibroinflammatory mass composed of a variable combination of myofibroblasts and inflammatory cells including lymphocytes and plasma cells. The disorder is composed of distinct histologic subtypes including the (1) cellular-type inflammatory myofibroblastic tumor, (2) plasma cell-rich type (plasma cell granuloma), and (3) fibrohistiocytic-type with foamy macrophages.

On the basis of pathologic findings in a series of 9 patients, Zen et al (1) postulated that the plasma cell-rich subtype of pulmonary inflammatory pseudotumors may be a manifestation of IgG4-related systemic disease. Clinically, these patients were often asymptomatic and presented with fairly well circumscribed solitary nodules on chest x-ray or computed tomography (CT) scan. Two patients presented with endobronchial nodules. An interesting finding was the presence of marked uptake within the nodule and regional nodes on positron emission tomography scan, performed on 1 patient, which mimicked malignancy radiographically. Serum IgG4 levels were not assessed.

Histologically, the nodules had features of the plasma cell-rich variant of inflammatory pseudotumor. They showed a combination of irregular fibrosis with numerous admixed lymphocytes and plasma cells. Upon immunohistochemical examination, there were increased numbers of IgG4-positive plasma cells compared to the numbers for control patients with idiopathic interstitial pneumonia (62-235 IgG4-positive plasma cells per high-power field compared to 0-7 such cells for control patients). Similarly, the ratio of IgG4-positive to IgG plasma cells was markedly elevated in all cases compared to controls (56.5% [+ or -] 12.5 versus 3.4 [+ or -] 0.4).

In addition to elevated numbers of plasma cells, all cases showed easily identifiable obliterative phlebitis on Verhoeff-van Gieson elastic tissue stain. Obliterative arteritis was identified in 5 of 9 cases. Other histologic findings variably present included an interstitial pneumonia pattern at the boundary of the nodules, lymphoplasmacytic chronic bronchiolitis with associated stenosis, lymphoid follicles, prominent eosinophilic infiltration, focal areas of obstructive pneumonia, multinucleated giant cells, and focal accumulations of neutrophils. In addition to the pulmonary lesions, increased numbers of IgG4-positive plasma cells were present in regional nodes and in areas of chronic sclerosing sialadenitis of 1 patient. (1)

Treatment for most of the patients in the study of Zen et al (1) consisted of resection--partial or sometimes complete lobectomy. In 1 patient, inflammatory pseudotumor was diagnosed on transbronchial biopsy. In this case, the nodule resolved after steroid therapy, with only a small fibrous scar remaining on radiologic studies.

Tsuboi et al (11) reported the case of a 62-year-old man with a pulmonary inflammatory pseudotumor and bilateral pulmonary infiltrates. Histologically, a lung biopsy specimen showed a plasma cell-rich type of inflammatory pseudotumor. As in the study by Zen and colleagues, (1) this entity was associated with numerous IgG4-positive plasma cells. Clinically, this patient also had an elevated serum IgG4 level as well as involvement of the pancreas, retroperitoneum, and pituitary stalk. The patient's condition, including the pulmonary changes, responded readily to steroid therapy. (11)

In the series of Shrestha et al, (6) 4 of 10 patients with inflammatory pseudotumor also had increased numbers of IgG4-positive plasma cells. These findings lend additional support to the studies of both Zen et al (1) and Tusboi et al (11) and show that a subset of these patients has IgG4-related sclerosing disease. (6)

Interstitial Pneumonia With IgG4-Positive Plasma Cells

Interstitial pneumonia has been reported in association with autoimmune pancreatitis in some patients. Taniguchi et al (12) reported the case of a 63-year-old man with autoimmune pancreatitis who developed ground-glass opacities and basilar honeycombing, as observed on chest CT. This condition was associated with a markedly elevated serum IgG4 level. Transbronchial biopsy showed an alveolar septal inflammatory infiltrate containing numerous IgG4-positive plasma cells. The ground-glass infiltrates (but not areas of honeycombing) resolved rapidly after treatment with steroids.

Hirano et al (13) reported 4 cases of interstitial pneumonia occurring in patients during follow-up for autoimmune pancreatitis.

Kobayashi et al (14) reported the development of pulmonary infiltrates in a 61-year-old man with autoimmune pancreatitis and elevated serum levels of IgG4. Findings on high-resolution CT scan included bilateral perihilar alveolar consolidation with peripheral areas of ground-glass opacity and a masslike lesion around the left hilum. (14) Intra-alveolar organization and peribronchial lymphoplasmacytic infiltrates were present on transthoracic needle and subsequent thoracoscopic lung biopsy. Numerous IgG4-positive plasma cells were present on immunohistochemistry.

Takato et al (7) reported the case of a 59-year-old man with an idiopathic interstitial pneumonia associated with elevated serum levels of IgG4 but without autoimmune pancreatitis. The patient had a 3-month history of cough, dyspnea, and bilateral pulmonary infiltrates. High-resolution CT scan showed bilateral ground-glass opacities and reticular shadows with areas of traction bronchiectasis and honeycomb-like changes in the lower lobes. Histologically, a thoracoscopic biopsy specimen showed a pattern of diffuse interstitial fibrosis and an associated lymphoplasmacytic infiltrate. On the basis of these observations, the authors suggested that some cases of idiopathic NSIP may be related to IgG4-related pulmonary disease.

In the series of Shrestha et al (6) consisting of 18 patients with pulmonary involvement by IgG4-related sclerosing disease, areas of cellular or mixed cellular and fibrosing NSIP pattern were present at least focally in many biopsy specimens. In addition, 8 of 61 biopsy specimens from patients with a variety of interstitial and inflammatory lung disease, not otherwise specified, were associated with an increased number of plasma cells (range, 11-99/3 high-power fields) as well as an increased IgG4 to IgG plasma cell ratio (range, 14%-71%). In conjunction with prior case reports, these observations also suggest that some cases of idiopathic chronic interstitial lung disease may be manifestations of IgG4-related sclerosing disease.

Is Grade I Lymphomatoid Granulomatosis Associated With IgG4-Related Sclerosing Disease?

A recent study (8) has suggested that some cases formerly considered grade I lymphomatoid granulomatosis (or alternatively benign lymphocytic angiitis and granulomatosis) are distinct from grade II and grade III lymphomatoid granulomatosis and actually represent pulmonary manifestations of IgG4-related sclerosing disease. In this study, Yamashita et al (8) reported 3 patients with interstitial lymphoplasmacytic interstitial infiltrates associated with arteritis and venulitis. One patient was asymptomatic, whereas 2 others reported dyspnea. Vague nodular densities or bilateral areas of consolidation were present radiographically. Positron emission tomography results were positive for 1 patient. Serum levels of IgG4 were elevated in the 1 patient for whom they were measured.

Histologically, in addition to the interstitial lymphoplasmacytic infiltrate, areas of arteritis and venulitis, consisting of permeation of the subendothelium by numerous lymphocytes and plasma cells, were accompanied by narrowing or obliteration of the vascular lumina. On immunohistochemistry, there were markedly increased numbers of IgG4-positive plasma cells with an IgG4 to IgG plasma cell ratio of 46% to 85%. In contrast to grade II or III lymphomatoid granulomatosis, atypical lymphocytes were not identified. In situ hybridization for Epstein-Barr virus was either not observed or observed in only rare small lymphocytes. (8)

In addition to the cases in this report, similar cases have been identified in prior reports, 2 of which were associated with autoimmune pancreatitis. (15,16) On the basis of these findings, Yamashita et al (8) suggested that lesions of grade I lymphomatoid granulomatosis may be a pulmonary manifestation of IgG4-related sclerosing disease.

Sclerosing Mediastinitis

Sclerosing mediastinitis consists of a fibroinflammatory mass within the mediastinum that often secondarily obstructs the trachea and bronchi, esophagus, and veins. It mimics malignancy both clinically and radiographically. The etiology of sclerosing mediastinitis is varied. Major causes have included infection (Histoplasma capsulatum, other fungi, tuberculosis), sarcoidosis, and trauma and may also be idiopathic. Recent reports suggest that some idiopathic cases may be a manifestation of IgG4-related sclerosing disease.

Inoue et al (9) reported a case of sclerosing mediastinitis accompanied by high serum levels of IgG4. The patient was a 56-year-old woman with exertional dyspnea and a diffuse mass in the posterior mediastinum on CT scan that entrapped the esophagus, bronchi, and azygos vein. A biopsy of the mass showed numerous IgG4-positive plasma cells. Both the mass and the patient's symptoms resolved after treatment with steroids.

Zen et al (10) reported a similar case involving a 52-year-old man with a combination of retroperitoneal and mediastinal fibrosis. Like the case reported by Inoue et al, (9) serum levels of IgG4 were elevated and a biopsy from the retroperitoneal mass showed numerous IgG4-positive plasma cells. Both retroperitoneal fibrosis and mediastinal fibrosis responded readily to treatment with steroids. (10)

In both cases, mediastinal fibrosis occurred in the absence of autoimmune pancreatitis. I recently observed a similar case involving a 78-year-old man with a superior mediastinal mass encasing the left subclavian artery (Figure 1, h through j). The observations suggest that idiopathic cases of sclerosing mediastinitis may sometimes be a manifestation of IgG4-related sclerosing disease.


The pathogenesis of either systemic IgG4-related sclerosing disease or its pulmonary manifestations is not clearly understood. The findings of increased serum levels of IgG4 as well as increased numbers of IgG4-positive plasma cells in affected tissues suggest a central role for IgG4 in the development and evolution of the disorder. Nonetheless, more specific mechanisms are unclear.

IgG4 is the rarest IgG isotype and accounts for only 3% to 6% of total serum IgG. Generation of IgG4 is thought to be cytokine Th2 dependent and results from the effects of interleukin 4 on native B cells that direct them to switch to IgG4 and IgE. Unlike other IgG subclasses, it cannot activate complement and does not bind to C1q. (17-20) In separate studies, Okazaki et al (21) and Zen et al (22) have proposed important roles for either Th1 or Th2 immune reactions. Additional research is needed to confirm and extend these observations. (2,21,22)


Diffuse lymphoid hyperplasia encompasses follicular bronchiolitis and lymphoid interstitial pneumonitis (LIP) as part of a spectrum of hyperplasia of the bronchus-associated lymphoid tissue (BALT). The patterns frequently occur together and have similar clinical features and etiologies.


Follicular bronchiolitis refers to a pattern of numerous reactive lymphoid follicles in a peribronchial/peribronchiolar distribution. It may occur either alone or as a

secondary finding in association with bronchiectasis, chronic bronchitis, asthma, and other conditions. Follicular bronchiolitis principally occurs in 3 settings: (1) underlying collagen vascular disease, especially rheumatoid arthritis; (2) underlying immunodeficiency--both congenital or acquired such as acquired immunodeficiency syndrome (AIDS), common variable immune deficiency, or others; and (3) an idiopathic group. (23,24)


Follicular bronchiolitis may occur in patients of any age, from infants to the older population. Patients without associated collagen vascular disease or immunodeficiency tend to be middle-aged or older (range, 38 to 77 years; average, 54 years).23 Pulmonary symptoms include cough, dyspnea, fever, recurrent pneumonia, weight loss, or fatigue. (23,24) Results from pulmonary function studies may be normal or show a restrictive, obstructive, or mixed pattern. Serologic studies may show rheumatoid factor in patients with underlying collagen vascular disease. Hypergammaglobulinemia or hypogammaglobulinemia may also be present. (23)

The main findings on high-resolution CT scan consist of bilateral centrilobular and sometimes peribronchial nodules. Nodules are often less than 3 mm in diameter but may be as large as 12 mm in some cases (Figure 2, a).25

Pathologic Features

In follicular bronchiolitis, numerous lymphoid follicles with associated reactive germinal centers are present around bronchi and bronchioles. The bronchiolar lumens are sometimes compressed. Lymphocytes extend into and permeate the adjacent bronchial or bronchiolar epithelium (Figure 2, b through d; Table 2). Foci of organizing pneumonia, obstructive pneumonia, or a bronchiolar intraluminal neutrophilic exudate are sometimes present as nonspecific associated findings. (23) A mild, often inconspicuous, associated interstitial inflammatory infiltrate is often present in adjacent alveolar septa. The interstitial inflammatory infiltrate is prominent in about 20% of cases. In these cases, there is histologic overlap with LIP. (26) In some cases, lymphoid follicles are present both around bronchi and bronchioles as well as in a lymphangitic distribution along the interlobular septa and pleura. Cases with these features are sometimes described by the term diffuse lymphoid hyperplasia. (23)



The reactive lymphoid follicles stain positively for pan B-cell markers (CD20, CD79a), whereas the interstitial component, when present, stains positively for pan T-cell markers (CD3). Staining for BCL-2 is absent in reactive germinal centers but present in interstitial T cells. A polyclonal pattern is present on polymerase chain reaction (PCR) for IgH gene rearrangement. (26)

Follicular bronchiolitis should be distinguished from LIP, nodular lymphoid hyperplasia, and low-grade BALT lymphoma. (23) Although LIP may contain reactive germinal follicles, these are usually overshadowed by the prominent interstitial inflammatory infiltrate of T cells. Nonetheless, the histologic features of LIP and follicular bronchiolitis overlap, and the distinction may, in some cases, be arbitrary. Both patterns are considered part of the spectrum of lymphoid hyperplasia of the BALT. (26,27)

Nodular lymphoid hyperplasia is easily distinguished from follicular bronchiolitis by its radiographic and histologic features. In contrast to follicular bronchiolitis, nodular lymphoid hyperplasia presents as a single or multiple mass on imaging studies. Histologically, the confluent proliferation of germinal centers with interfollicular plasma cells present in nodular lymphoid hyperplasia contrasts with the peribronchial/peribronchiolar distribution of reactive follicles in follicular bronchiolitis. (28)

Low-grade B-cell lymphoma of BALT also generally presents as a well-demarcated solitary or multiple mass. Unlike either follicular bronchiolitis or nodular lymphoid hyperplasia, low-grade B-cell lymphoma of BALT is characterized by fairly monomorphous infiltrate of B lymphocytes. Reactive germinal centers may be present but are randomly distributed and are less prominent than the monomorphous B-cell infiltrate. Areas of cartilage invasion and plaquelike invasion of the pleura may also be present--features not present in follicular bronchiolitis. (29) Analysis by PCR may be helpful in some cases, as approximately 60% to 70% of low-grade BALT lymphomas will show a clonal rearrangement of the immunoglobulin heavy chain gene, whereas a polyclonal pattern is always present in nodular lymphoid hyperplasia and follicular bronchiolitis. (30)


The association of follicular bronchiolitis with immunodeficiency, collagen vascular disease, and peripheral eosinophilia suggests that it represents an expansion of the bronchus-associated lymphoid tissue in reaction to intrinsic and extrinsic stimuli. This theory is supported by some animal models showing the development of follicular bronchiolitis upon exposure to Mycoplasma pneumoniae, pseudomonas, and intratracheal bacille Calmette-Guerin. (23,31-33)

Prognosis and Treatment

The prognosis of idiopathic cases of follicular bronchiolitis is generally favorable. Most patients respond to steroids or azathioprine, although the patients may relapse. (23,24,34) Treatment and prognosis of patients with underlying collagen vascular disease or immunodeficiency is dependent upon the underlying condition.


Lymphocytic interstitial pneumonitis is a pattern of interstitial lung disease characterized by a polymorphous inflammatory infiltrate that diffusely expands alveolar septa. First described by Liebow and others in the early 1970s, (35,36) it is currently considered, along with follicular bronchiolitis, as part of the spectrum of pulmonary lymphoid hyperplasia. (26,27,37)

The LIP pattern may occur in association with underlying collagen vascular disease, immunodeficiency, allogeneic bone marrow transplantation, and drug reactions. (34,38) In associated collagen vascular diseases, LIP is a common manifestation of Sjogren syndrome, (39) but may also occur with rheumatoid arthritis (40) and systemic lupus erythematosus. (41,42) Lymphocytic interstitial pneumonitis has also been observed in patients with AIDS and common variable immunodeficiency. (34,43)--younger than 13 years who are infected with the human immunodeficiency virus (HIV), LIP is considered an AIDS-defining illness. (49) Rarely, LIP may be idiopathic.

In recent years, the diagnosis of LIP has been greatly restricted. Many of the cases formerly interpreted as LIP would now be considered examples of cellular NSIP. (34)

Lymphocytic interstitial pneumonitis affects persons in a broad age range, from infants to the elderly. However, most patients are middle-aged with a mean age at diagnosis of 52 to 56 years. Symptoms are nonspecific and include cough and dyspnea. The onset of symptoms is often gradual and may be present for years before diagnosis. (26,34,36,37)

Pulmonary function studies usually show a restrictive pattern. Carbon monoxide diffusing capacity is reduced. Arterial blood gases may show hypoxemia. A serum dysproteinemia consisting of a polyclonal hypergammaglobulinemia is present in up to 80% of patients. Some patients have hypogammaglobulinemia. (37)

High-resolution CT scans show bilateral areas of ground-glass opacity accompanied by centrilobular and subpleural nodules and patchy bronchovascular and interlobular septal thickening. A common associated finding is the presence of cysts, which, rarely, may dominate the radiographic findings. (37,50,51) Findings on chest x-ray are less specific and show bilateral lower zone reticular or reticulonodular infiltrates. (37)

Pathologic Features

The LIP pattern consists of a dense polymorphous interstitial inflammatory infiltrate that diffusely expands alveolar septa (Figure 3, a and b; Table 3). The infiltrate is composed of lymphocytes admixed with variable numbers of histiocytes and plasma cells. A component of follicular bronchiolitis is often present, consisting of reactive lymphoid follicles along bronchovascular bundles. 26,27,36 There is substantial overlap between the patterns of follicular bronchiolitis and LIP such that, in about 20% of cases, the distinction is arbitrary. (26,34) Other histologic features that may be present include intraepithelial lymphocytes, type II pneumocyte hyperplasia, focal lymphocytic infiltration of vessel walls, foci of organizing pneumonia, loose nonnecrotizing granulomas, and occasional isolated giant cells. Interstitial fibrosis of varying degree may be present. Foci of amyloid may also occur occasionally. (26,27,34,36)

On immunohistochemistry, interstitial lymphocytes are composed predominantly of T cells and stain positively for CD3 (pan T-cell marker). In contrast, areas of follicular bronchiolitis are composed of B cells and stain positively for CD20 and CD79a (pan B-cell markers). (26) Associated interstitial plasma cells show a polyclonal pattern of expression for k and l light chains and a polyclonal pattern on PCR for the IgH chain gene. (26,52)

The differential diagnosis of LIP is broad. Histologic considerations include follicular bronchitis/bronchiolitis, cellular NSIP, low-grade B-cell lymphomas (low-grade Bcell lymphoma of BALT and pulmonary involvement by chronic lymphocytic leukemia), hypersensitivity pneumonitis, and infection. Consideration of clinical and histologic features along with immunohistochemical and molecular studies, when appropriate, usually allows these disorders to be distinguished.

While LIP shows a predominantly interstitial infiltrate of T cells (CD3+), follicular bronchiolitis consists of peribronchial reactive lymphoid follicles expressing B-cell markers ([CD20.sup.+]). (26) Although extension of lymphocytes into the adjacent interstitium may be present in follicular bronchiolitis, it is usually not extensive. (23) Nonetheless, in occasional cases with overlapping histologic features, the distinction may be somewhat arbitrary. (26,27)

In contrast to the polymorphous interstitial infiltrate in LIP, interstitial patterns of low-grade B-cell lymphoma have a monomorphous appearance. Areas of cartilage invasion or plaquelike involvement of the pleura may be present in low-grade B-cell lymphoma but are generally absent in LIP. Likewise, Dutcher bodies are present in some cases of low-grade B-cell lymphoma but are not a feature of LIP. (34,53-55) On immunohistochemistry, low-grade B-cell lymphoma expresses pan B-cell markers (CD20, CD79a), whereas the interstitial infiltrate in LIP consists predominantly of T cells (CD3).26,56 Finally, in most, but not all cases of low-grade B-cell lymphoma, immunohistochemical and molecular studies show a clonal population of B cells.53 The presence of a clonal population can be demonstrated by either light chain restriction on immunohistochemistry for k and l chains or a clonal rearrangement on PCR for the IgH chain gene. A clonal population is not present in cases of LIP. (26)

Other forms of interstitial lung disease, such as cellular NSIP and hypersensitivity pneumonitis, must be distinguished from LIP. The distinction of cellular NSIP and LIP patterns is based primarily on the degree of cellular infiltration. The infiltrate in LIP is generally much more extensive than in cellular NSIP, such that it expands and distorts the underlying alveolar framework. In addition, reactive lymphoid follicles are also often present. Nonetheless, many cases formerly regarded as LIP would now be considered within the spectrum of cellular NSIP. (57) Poorly formed granulomas may be observed in both LIP and hypersensitivity pneumonitis. However, the interstitial infiltrate in hypersensitivity pneumonitis is patchy and less dense, with a peribronchiolar distribution. (34)

Infectious process can occasionally mimic an LIP pattern. Pneumocystis jiroveci pneumonia or cytomegalovirus may show a prominent interstitial mononuclear infiltrate. Accordingly, before considering a diagnosis of LIP on a surgical biopsy specimen, special stains as well as careful assessment for viral cytopathic effect should be performed. (34,58)


Lymphocytic interstitial pneumonitis is considered, along with follicular bronchiolitis, as part of a spectrum of hyperplasia of the BALT. The observation of LIP in association with Sjogren syndrome, EBV infection, and HIV infection likely reflects sequella of longstanding chronic antigen stimulation. (26,27,43,59)

Prognosis and Treatment

Approximately 33% to 50% of patients with LIP die within 3 to 5 years. However, prognosis depends somewhat on the associated underlying disease condition. In some patients the disease stabilizes or resolves. Mortality is the result of progressive honeycomb fibrosis or infectious complications. (37,59) Low-grade B-cell lymphoma may develop in rare cases. (52)

Treatment consists of steroids or other immunosuppressive agents, with variable results. Single and multidruga ntiretroviral therapy may induce remission in HIV-infected patients. (37)




Nodular lymphoid hyperplasia consists of a reactive nodular lymphoid proliferation that presents as 1 or more pulmonary masses. Most cases diagnosed as pulmonary "pseudolymphomas" in the past would now be considered low-grade B-cell lymphoma of BALT. (29,60) Nonetheless, nodular lymphoid hyperplasia refers to those cases that are reactive when stringent histologic, immunophenotypic, and genotypic criteria are applied. (28,30)

Clinical Features

Most patients are asymptomatic and present with a nodule or nodules identified incidentally on chest x-ray. When symptoms are present, they are nonspecific and include cough, dyspnea, and pleuritic chest pain. Nodular lymphoid hyperplasia occurs slightly more often in females than males by a ratio of 4:3. Patients range in age from 19 to 80 years (median, 60 years). Mediastinal or hilar adenopathy may be present in approximately one-third of patients. (28) Although initial reports (28) did not suggest an association with collagen vascular disease, a more recent report (61) has identified nodular lymphoid hyperplasia in a patient with Sjogren syndrome.

Pathologic Features

Gross features of nodular lymphoid hyperplasia consist of well-circumscribed gray to white tan nodule(s). Multiple nodules are present in one-third of cases. The nodules are often subpleural but may also be peribronchial. 28

Histologically, nodular lymphoid hyperplasia is well demarcated and composed of numerous reactive germinal centers with sheets of interfollicular plasma cells (Figure 4, a; Table 4). Reactive germinal centers may be present within alveolar septa. Begueret and colleagues (30) identified lymphoepithelial lesions in 60% of their cases, although these lesions were not present in the series of Abbondanzo et al. (28) Interfollicular fibrosis is often present and may be extensive, partially effacing the underlying pulmonary parenchyma (Figure 4, b). Rare cases may contain scattered giant cells. Dutcher bodies, bronchial cartilage invasion, or plaquelike involvement of the pleura are not identified. (28)

Immunohistochemical and molecular studies may be helpful in distinction from low-grade B-cell lymphoma. The reactive lymphoid follicles stain positively for B-cell markers (CD20 and CD79a), while interfollicular lymphocytes stain predominantly for T-cell markers (CD3, CD43, and CD5). Unlike many cases of low-grade B-cell lymphoma, coexpression of CD20 and CD43 by lymphocytes is not identified either within the parenchyma or in lymphoepithelial lesions. (28,30) Expression of BCL-2 is absent in germinal centers and limited to mantle zone and interfollicular lymphocytes. A polyclonal pattern of expression is present in interfollicular plasma cells on stains for k and l light chains. A polyclonal pattern is also present on PCR analysis for the immunoglobulin heavy chain gene. (28)

Differential Diagnosis

The differential diagnosis of nodular lymphoid hyperplasia includes LIP, follicular bronchiolitis, and low-grade B-cell lymphoma. These disorders can be distinguished by consideration of the clinical, radiographic, and histologic features. (28)

Radiographically, nodular lymphoid hyperplasia consists of well-demarcated nodules or masses in contrast to the diffuse reticulonodular or small nodular infiltrate of LIP. Histologically, there is a confluent proliferation of lymphoid follicles in nodular lymphoid hyperplasia. The infiltrate in LIP, on the other hand, diffusely expands the interstitium. Reactive lymphoid follicles are a more prominent and consistent feature in nodular lymphoid hyperplasia. (28)

Follicular bronchiolitis is also distinct. Radiographically, bilateral centrilobular and sometimes peribronchial nodules are present on CT scan. In contrast, the nodules present in nodular lymphoid hyperplasia are generally larger, well demarcated, and often solitary with a subpleural predilection. Histologically, follicular bronchiolitis shows lymphoid follicles with reactive germinal centers in a peribronchial or peribronchiolar distribution. As with features on imaging studies, a mass or nodule is not present histologically. (28)

Distinction of nodular lymphoid hyperplasia from low-grade B-cell lymphoma may be more problematic. Imaging studies of both nodular lymphoid hyperplasia and low-grade B-cell lymphoma are similar and show 1 or more well-defined nodules. Histological, immunohistochemical, and molecular features, however, usually allow their separation. In nodular lymphoid hyperplasia, in contrast to BALT lymphoma, cases show only focal (not extensive) tracking of lymphatics and usually no plaque-like involvement of the pleura. Coexpression of CD20 and CD43 by lymphocytes may sometimes be present in low-grade B-cell lymphoma but is not identified in nodular lymphoid hyperplasia. Plasma cells in nodular lymphoid hyperplasia show a polyclonal pattern of immunohistochemical staining for k and l chains. On the other hand, light chain restriction is identified in a significant proportion of cases of low-grade B-cell lymphoma. Likewise, immunoglobulin heavy chain gene rearrangement can often be demonstrated in low-grade BALT lymphoma, but it is not present in nodular lymphoid hyperplasia. (28,30)


The pathogenesis of nodular lymphoid hyperplasia is unknown. The observation of a subpleural predilection, similar to intrapulmonary lymph nodes, suggests the possibility of an aberrant organization of BALT, possibly reflecting the effects of an antecedent inflammatory event. Unlike follicular bronchiolitis and LIP, most cases appear unassociated with connective tissue disease, immunodeficiency, or prior viral infection. (28)

Prognosis and Treatment

Nodular lymphoid hyperplasia is a benign lesion. Surgical excision is generally curative. (28)


Advances in imaging technology have enhanced the detection of pulmonary lymph nodes. They may be biopsied to exclude the possibility of carcinoma. (62)

Clinical Features

Patients are asymptomatic or have symptoms related to another disease. A nodule is often detected incidentally on radiographic studies. Most patients are smokers. In 1 autopsy study, intraparenchymal lymph nodes were found in 18% of patients. (63,64)

Radiographic Features

On radiographic studies, intrapulmonary lymph nodes usually consist of well-circumscribed nodules in a subpleural or paraseptal location. They may occasionally have irregularities or spiculation leading to their biopsy. (62)

Pathologic Features

Gross findings of intraparenchymal lymph nodes reflect their radiographic features. They appear as solid, subpleural, round to oval nodules, ranging in size up to 12 mm with a subpleural or paraseptal distribution. Histologically, intrapulmonary lymph nodes are identical to lymph nodes in other parts of the body (Figure 5; Table 5).64

Differential Diagnosis

The diagnosis of intrapulmonary lymph nodes is usually straightforward. The differential diagnosis includes nodular lymphoid hyperplasia and intrapulmonary thymoma. In contrast to intrapulmonary lymph nodes, nodular lymphoid hyperplasia is usually larger (2-4 cm) and lacks the architecture of a lymph node. (28) Intrapulmonary thymoma is similar to mediastinal thymomas. These tumors contain variable mixtures of epithelial cells and lymphocytes usually subdivided into lobules by fibrous bands. The presence of admixed epithelial cells can be highlighted on immunohistochemical staining for cytokeratin and helps to confirm the diagnosis. Metastatic carcinoma should be sought in patients with known lung cancer in other areas.


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Donald G. Guinee Jr, MD

Accepted for publication September 3, 2009.

From the Department of Pathology, Virginia Mason Medical Center, Seattle, Washington.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Donald G. Guinee Jr, MD, Department of Pathology, C6PTH, Virginia Mason Medical Center, 1100 9th Ave, Seattle, WA 98101 (e-mail:
Table 1. Thoracic Manifestations of IgG4-Related Systemic Disease (a)

Fibroinflammatory mass with lymphangitic distribution
Plasma cell-rich variant of inflammatory pseudotumor
Cases formerly thought to represent grade I lymphomatoid granulomatosis
(not grade II or grade III lesions)
NSIP pattern (some cases)
Sclerosing mediastinitis (some cases)

Abbreviation: NSIP, nonspecific interstitial pneumonia.

(a) These categories are preliminary and drawn from isolated case
reports and small series.

Table 2. Histopathologic Features of
Follicular Bronchitis/Bronchiolitis

Major features
  Reactive lymphoid follicles present adjacent to bronchi and
  Lymphoid follicles stain positively for pan B-cell markers
    CD20 and CD79a
  In some cases histologic features may overlap with LIP
Secondary features
  Foci of organizing pneumonia
  Foci of obstructive pneumonia
  Bronchiolar intraluminal neutrophilic infiltrate
  Cases may be associated with lymphoid follicles in a
  lymphangitic distribution along interlobular septa and
  pleura (diffuse lymphoid hyperplasia)

Abbreviation: LIP, lymphocytic interstitial pneumonia.

Table 3. Histopathologic Features of Lymphocytic
Interstitial Pneumonia

Major features
  Dense polymorphous interstitial inflammatory infiltrate
    composed of lymphocytes, histiocytes, and plasma cells
  Component of follicular bronchiolitis often present
Secondary features
  Intraepithelial lymphocytes
  Type II pneumocyte hyperplasia
  Focal lymphocytic infiltration of vessel walls
  Foci of organizing pneumonia
  Loose nonnecrotizing granulomas
  Occasional giant cells
  Interstitial fibrosis of variable degree
  Foci of amyloid

Table 4. Histopathologic Features of Nodular
Lymphoid Hyperplasia

Major features
 Well-demarcated mass (or masses) consisting of numerous
   reactive lymphoid follicles with germinal centers
 Sheets of interfollicular plasma cells
 Plasma cells are polyclonal on immunohistochemical
   staining for k and l light chains
Secondary features
   Interfollicular fibrosis may be present, of variable degree

Table 5. Histopathologic Features of
Intraparenchymal Lymph Nodes

Major features
  One or multiple
  Subpleural or paraseptal distribution
  Similar features to normal lymph nodes
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Author:Guinee, Donald G., Jr.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:May 1, 2010
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