Update in Nonneoplastic Lung Diseases - Archives of Pathology and ...

Update in Nonneoplastic Lung Diseases Ilyssa O. Gordon, MD, PhD; Nicole Cipriani, MD; Qudsia Arif, MB; A. Craig Mackinnon, MD, PhD; Aliya N. Husain, MD

● Context.—Nonneoplastic lung diseases include a wide range of pathologic disorders from asthma to interstitial lung disease to pulmonary hypertension. Recent advances in our understanding of the pathophysiology of many of these disorders may ultimately impact diagnosis, therapy, and prognosis. It is important for the practicing pathologist to be aware of this new information and to understand how it impacts the diagnosis, treatment, and outcome of these diseases. Objective.—To update current progress toward elucidating the pathophysiology of pulmonary alveolar proteinosis, idiopathic pulmonary hemosiderosis, and pulmonary arterial hypertension, as well as to present classification systems for pulmonary hypertension, asthma, and intersti-

tial lung disease and describe how these advances relate to the current practice of pulmonary pathology. Data Sources.—Published literature from PubMed (National Library of Medicine) and primary material from the authors’ institution. Conclusions.—Improved understanding of the pathophysiology of pulmonary alveolar proteinosis, pulmonary hypertension, and idiopathic hemosiderosis may impact the role of the surgical pathologist. New markers of disease may need to be assessed by immunohistochemistry or molecular techniques. The classification systems for interstitial lung disease, asthma, and pulmonary hypertension are evolving, and surgical pathologists should consider the clinicopathologic context of their diagnoses of these entities. (Arch Pathol Lab Med. 2009;133:1096–1105)

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the pathophysiology of nonneoplastic lung disease will also greatly aid in the goal of arriving at a correct diagnosis. Recent discoveries in diseases such as pulmonary alveolar proteinosis, idiopathic pulmonary hemosiderosis, and pulmonary arterial hypertension may impact the diagnosis of these diseases, and new prognostic markers or therapeutic targets identifiable by immunohistochemistry may be requested by clinicians. Also, classification systems of nonneoplastic lung diseases are evolving as we understand more about disease pathophysiology. A new clinical classification system for pulmonary hypertension must be reconciled against our current understanding of the histologic changes that characterize this group of diseases. Asthma classifications based on inflammatory cell make-up are coming into use as well. Finally, revisions to the American Thoracic Society/ European Respiratory Society (ATS/ERS) classification of interstitial lung disease have been published recently, and understanding the features of each diagnostic category of interstitial lung disease is necessary for clinicopathologic correlation.

iagnosis of nonneoplastic lung diseases can be challenging for surgical pathologists. Many diseases in this category are rare, and even conditions that are common are not often examined by biopsy. A directed approach to the assessment of a lung biopsy (usually a wedge) for suspected nonneoplastic lung disease begins in the gross room. Because infectious processes are frequently part of the differential diagnosis, tissue for cultures should be sent to the microbiology laboratory, preferably directly from the operating room since contamination is less likely than from the gross room. In pediatric cases, it is essential to fix a portion of fresh tissue in glutaraldehyde for electron microscopic studies. The biopsy specimen should be serially sectioned and submitted in toto. Assessment of the microscopic hematoxylin-eosin sections should be done systematically to include pleura, interstitium, alveolar space and airway, and vessels (arteries, veins, and lymphatics). Attention should also be paid to the location of pathologic findings—whether focal or diffuse, subpleural or central—and differences in severity from lobe to lobe in cases where more than 1 lobe is sampled. By following these principles, most nonneoplastic lung diseases can be adequately diagnosed and pitfalls leading to incorrect diagnoses can be avoided. Keeping abreast of the latest advances in understanding Accepted for publication December 15, 2008. From the Department of Pathology, University of Chicago, Chicago, Illinois. Presented in part at the Current Issues in Diagnostic Pathology conference, University of Chicago, Chicago, Illinois, November 2006. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Aliya N. Husain, MD, Department of Pathology, University of Chicago, MC6106, Room S627, 5841 S Maryland Ave, Chicago, IL 60637 (e-mail: [email protected]). 1096 Arch Pathol Lab Med—Vol 133, July 2009

PULMONARY ALVEOLAR PROTEINOSIS Pulmonary alveolar proteinosis (PAP) is a rare disorder of alveolar accumulation of lipoproteinaceous surfactant components. The 3 general categories of PAP, namely congenital, idiopathic, and secondary, have various and possibly overlapping etiologies. Most cases of PAP occur in adults and are idiopathic (90%). In the past decade, major advances in our understanding of the pathophysiology of congenital and idiopathic PAP have been made. Congenital PAP (Surfactant-Deficiency Diseases) Congenital PAP is rare and often involves genetic defects of surfactant proteins or proteins involved in surfactant processing and homeostasis.1,2 Surfactant, a combiUpdate in Nonneoplastic Lung Diseases—Gordon et al

nation of proteins and phospholipids normally generated and secreted by type II pneumocytes starting in the weeks before birth, lines the alveolar surface of the lungs to reduce surface tension and to prevent alveolar collapse with expiration, and its components are eventually cleared by alveolar macrophages. Clinical history, including family history of pulmonary disease and age at onset of symptoms, may be helpful in directing the diagnostic evaluation and determining the molecular or genetic etiology of congenital PAP. More than 30 different inherited autosomal recessive mutations of the gene encoding surfactant protein (Sp) B have been identified,2 but the most common mutation is caused by a 2-bp insertion in exon 4 (121ins2), resulting in a frameshift mutation with a premature stop codon and failure of production of mature Sp-B.1 Surfactant protein B is protective against oxygen-induced lung injury3 and its deficiency is associated with Sp-A and Sp-C accumulation within type II pneumocytes4 and in alveolar spaces,1 through mechanisms which are not entirely clear. These patients also have been shown to have abnormal processing of Sp-C, which further contributes to its accumulation.5 Alveolar gas exchange is markedly impaired, resulting in severe respiratory distress and death. Compound heterozygotes typically have only a partial Sp-B deficiency, which results in milder symptoms and longer survival.6 Recently discovered autosomal dominant genetic defects result in an ABCA3 protein that leads to impaired surfactant processing. These genetic defects elucidate an interesting mechanism, which may lead to the clinical and histopathologic features of an early and aggressive form of congenital PAP.7 The ABCA3 gene encodes a lipid transporter expressed mainly on the limiting membrane of lamellar bodies in type II pneumocytes, the site of surfactant processing and storage.8 Genetic defects result in reduced or absent surfactant protein expression and characteristic ultrastructural features including abnormal lamellar bodies with eccentric dense cores (Figure 1). Patients have a poor prognosis even with maximal support. Compound heterozygotes may have a better prognosis with later onset of symptoms.9 Less commonly, various genetic mutations of Sp-C can cause congenital PAP.10 Surfactant protein C mutations can be inherited in an autosomal dominant manner or can be sporadic, with variable age at onset of clinical symptoms and variable histologic findings.2 Rare cases of congenital PAP have been shown to be due to defective expression of the common ␤c chain subunit of the granulocyte monocyte–colony stimulating factor (GM-CSF) receptor,11 resulting in a functional deficiency of GM-CSF. Idiopathic PAP The most significant recent advance in our understanding of PAP has been the identification of a neutralizing autoantibody to GM-CSF in patients with the idiopathic form of the disease. The involvement of GM-CSF in human PAP was suspected after it was observed that GMCSF⫺/⫺ mice developed alveolar accumulations of lipoproteinaceous material and debris, similar to that seen in PAP.12,13 Deficiency of GM-CSF (Figure 2) was found to result in severely impaired Sp-A and phosphatidylcholine clearance from the lungs, resulting in alveolar phospholipid stasis and accumulation.14 The catabolism of Sp-A and phosphatidylcholine by alveolar macrophages was Arch Pathol Lab Med—Vol 133, July 2009

Figure 1. Congenital pulmonary alveolar proteinosis. This electron micrograph shows abnormal lamellar bodies with eccentric electron dense cores in the cytoplasm of a type II pneumocyte from a 5-weekold patient and are typical of an ABCA3 mutation (original magnification ⫻15 500).

impaired, despite increased uptake of these accumulating phospholipids.15 This functional defect of alveolar macrophages is thought to be due to their immature state because of decreased expression of the transcription factor PU.1,16 which is important for myeloid cell growth and differentiation.17,18 Expression of PU.1 in alveolar macrophages is increased by GM-CSF.19 A more recent study has shown that in contrast to other tissue macrophages, alveolar macrophages are unique in their dependence on PU.1 for terminal differentiation, which explains why the effects of anti–GM-CSF in patients with PAP is localized to the lungs.20 Dysregulation of lipid metabolism and transport in alveolar macrophages has also been found in patients with functional GM-CSF deficiency.21,22 Secondary (Acquired) PAP The pathophysiology of secondary PAP has not been thoroughly investigated. Environmental exposures may cause alveolar macrophage impairment due to the presence of dusts or crystals, such as in PAP due to silicosis.11,23–25 Despite the well-known association of PAP with acute and chronic leukemias,26–29 mechanistic studies are lacking. Functionally defective alveolar macrophages or reduced alveolar macrophage progenitor cells due to cytopenia have been suggested as possible mechanisms.30 Patients with rare pediatric acute myeloid leukemia have been found to have PAP associated with defective leukemic cell expression of the common ␤c chain and ␣ chains of the GM-CSF receptor.29 A similar mechanism may explain the development of PAP in an adult with myelodysplastic syndrome who had increased levels of GM-CSF in bronchoUpdate in Nonneoplastic Lung Diseases—Gordon et al

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Figure 2. Functional granulocyte monocyte–colony stimulating factor (GM-CSF) deficiency in idiopathic pulmonary alveolar proteinosis. A, Normal macrophage responding to GM-CSF. B, Autoantibody neutralizing GM-CSF, resulting in decreased binding and decreased expression of the transcription factor PU-1 and leading to a relatively immature macrophage state and impaired catabolism of phosphatidylcholine and surfactant protein A.

alveolar lavage (BAL) fluid and no GM-CSF autoantibody.31 Pulmonary alveolar proteinosis associated with the rare autosomal recessive disorder lysinuric protein intolerance, in which there is defective cationic amino acid transport,32 may be due to common transporter defects resulting in imbalances of arginine and nitric oxide. Alternatively, there may be a defect in bone marrow–derived macrophages, as has been suggested in a case report of recurrent PAP in a patient with lysinuric protein intolerance after heart-lung transplant.33 Pathologic Features of PAP The pathologic features of PAP are similar, regardless of etiology, because they reflect the common finding of surfactant and phospholipid accumulation in the airspaces. Several serum and BAL fluid markers, which may correlate with disease activity, have been identified in patients with PAP, including the glycoprotein KL-6,34,35 LDH,36 IL-10,37 and the cholesterol metabolite cholestenoic acid.38 In patients with idiopathic PAP, serum and BAL anti–GM-CSF antibodies are disease-specific and BAL titers may correlate with other serologic, radiologic, and clinical disease parameters.39 Obtaining BAL fluid for analysis in patients with PAP offers a less invasive adjunct diagnostic tool. The characteristic microscopic finding is that of dense orange-brown globules with sharp green borders in ethanol-fixed, Papanicolaou-stained BAL preparations.40 The presence of 18 or more of these globules is highly sensitive and specific for PAP.41 Foamy macrophages and other inflammatory cells are sparse in the background.42 Although findings on BAL fluid may be characteristic, a wedge lung biopsy is considered the gold standard for diagnosis. Transbronchial biopsy may also yield diagnostic material. In idiopathic PAP, histologic sections show filling of the alveolar airspaces and some small bronchioles by amorphous granular eosinophilic material (Figure 3). Cellular debris, including degenerating alveolar mac1098 Arch Pathol Lab Med—Vol 133, July 2009

rophages, sloughed pneumocytes, and cholesterol clefts, is often present, and there may be a regenerative type II pneumocyte hyperplasia. The eosinophilic material is periodic acid-Schiff–positive with diastase digestion, mucicarmine negative, and immunohistochemically positive for surfactant proteins A, B, and C. The alveolar architecture is preserved, with minimal inflammation. Increased interstitial inflammation should prompt suspicion for a superimposed infectious process. Interstitial fibrosis may be present in longstanding disease. Surrounding alveoli may have secondary emphysematous change.43 In congenital PAP, the intra-alveolar material is often sparse and is immunohistochemically negative for Sp-B in cases due to genetic Sp-B deficiency. In addition, there are signs of impaired alveolarization, such as thickened alveolar interstitial septae, a simplified alveolar pattern, and regenerative hyperplastic type II pneumocytes1,2 (Figure 4). It should be noted that some cases of congenital PAP may have pathologic findings of desquamative interstitial pneumonitis on transbronchial biopsy, with typical PAP histologic findings only in subpleural areas.1,44 Cases of secondary PAP due to environmental exposures may show histologic evidence of the causative particles (Figure 5). Electron microscopic analysis of tissue sections and BAL fluid in idiopathic PAP reveals multilamellated tubular myelin-like and fused membrane lamellar bodylike structures, both in the airspaces and within alveolar macrophages.16,45–47 Crystals and evidence of cell debris can also be identified. In congenital PAP due to Sp-B deficiency, the lamellar bodies may be disorganized2 and decreased in number, and membranous vesicular debris from Sp-A, Sp-C, and type II pneumocytes may be found between type II cells and their basement membrane.48 Lamellar bodies in congenital PAP due to ABCA3 deficiency are decreased and have abnormal eccentric dense core bodies with a ‘‘fried-egg’’ appearance7,44 (Figure 1). Update in Nonneoplastic Lung Diseases—Gordon et al

Treatment of PAP Advances in our understanding of the pathophysiology of PAP are leading to new experimental therapies. Several studies have demonstrated treatment efficacy in the use of subcutaneous49,50 or aerosolized51 GM-CSF for patients with idiopathic PAP. Interestingly, the first successful treatment with GM-CSF of a patient with idiopathic PAP52 occurred before the identification of a neutralizing autoantibody to GM-CSF, when the rationale for administering GM-CSF was based on a suspected GM-CSF defect, as had been shown in mouse models.16 Although the actual mechanism has not been clearly elucidated, a reduction in the titer of anti–GM-CSF antibodies has been shown.53,54 Whole lung lavage remains the gold standard for treatment of idiopathic PAP. The mechanism is thought to be both physical removal of the accumulated lipoproteinaceous material, as well as removal of anti–GM-CSF antibodies.30 Congenital PAP is treated supportively, although whole lung lavage, aerosolized surfactant protein administration, intravenous immunoglobulin G administration,55 and lung transplantation are possible alternatives.56 Secondary PAP due to hematologic malignancy typically regresses with successful therapy of the underlying disorder,28,29 and cases with other etiologies can be treated with whole lung lavage.57,58 The median duration of response to whole lung lavage is 15 months,59 although single-institution studies reported that 46% to 62% of patients had sustained improvement after only a single whole lung lavage procedure.46,60 Disease specific survival at 5 years for patients with idiopathic PAP is 88%.59 Most case reports from patients with congenital PAP indicate a poor prognosis, with survival measured in days to months.56,61,62 IDIOPATHIC PULMONARY HEMOSIDEROSIS Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by heavy lungs with aggregates of hemosiderin-laden macrophages due to recurrent diffuse alveolar hemorrhage in the absence of vasculitis or capillaritis and by eventual interstitial fibrosis (Figure 6). Presentation is most often seen in the pediatric age group although adults can also be affected. Although the exact etiologic mechanisms remain unknown, IPH has been linked with certain household pathogenic molds and decreased levels of von Willebrand factor, suggesting an environmental trigger in genetically predisposed individuals.63 There have also been several case reports of IPH occurring in individuals with celiac disease,64–66 pointing to a possible autoimmune etiology. Untreated IPH has a poor prognosis, but use of corticosteroids in pediatric and adult patients has greatly improved outcomes,67–69 also suggesting an immune-mediated aspect to the pathophysiology of this disease. Figure 3. Idiopathic pulmonary alveolar proteinosis. Granular eosinophilic material is present within alveolar spaces. Note globules of proteinaceous material that correspond to the globules seen in cytologic preparations of bronchoalveolar lavage fluid (hematoxylin-eosin, original magnification ⫻100). Figure 4. Congenital pulmonary alveolar proteinosis. Relatively immature-appearing lung tissue shows marked type II pneumocyte hyperplasia, areas of intra-alveolar eosinophilic material, and focal fibrosis. Inset shows high-power view of intra-alveolar granular material with foamy macrophages (hematoxylin-eosin, original magnifications ⫻100 and ⫻400 [inset]). Arch Pathol Lab Med—Vol 133, July 2009

← Figure 5. Secondary pulmonary alveolar proteinosis due to silica. This 63-year-old man, who had worked as a sandblaster, presented with small bilateral effusions and upper-lobe nodules. The biopsy specimen showed alveolar spaces filled with abundant eosinophilic material with cholesterol clefts. Other sections showed silicotic nodules (hematoxylin-eosin, original magnification ⫻100). Courtesy of T. Colby, MD, Mayo Clinic, Scottsdale, Arizona. Update in Nonneoplastic Lung Diseases—Gordon et al

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Figure 6. Idiopathic pulmonary hemosiderosis. There is evidence of both recent and old hemorrhage (hemosiderin-laden macrophages). The inset shows abundant iron (hematoxylin-eosin, original magnification ⫻200; Prussian blue stain, original magnification ⫻200 [inset]). Figure 7. Idiopathic pulmonary arterial hypertension. In a branch of pulmonary artery, there is endothelial proliferation leading to formation of multiple lumina (plexiform lesion) with fibrin thrombi. Inset shows trichrome stain highlighting the intra-arterial tufting (hematoxylin-eosin, original magnification ⫻100; trichrome stain, original magnification ⫻200 [inset]).

PULMONARY HYPERTENSION Pulmonary hypertension is a clinical diagnosis encompassing a variety of diseases affecting the pulmonary vasculature, many of which have overlapping histologic features. The most recent World Health Organization clinical classification70,71 defines 5 groups of pulmonary hypertension: (1) arterial, (2) venous, (3) hypoxemia associated, (4) thrombotic-embolic associated, and (5) miscellaneous. The first group includes pulmonary arterial hypertensive conditions previously referred to as both primary (idiopathic pulmonary arterial hypertension, IPAH) and secondary (familial pulmonary arterial hypertension; associated with pulmonary arterial hypertension, APAH; and persistent pulmonary hypertension of the newborn, PPH). The use of the term idiopathic pulmonary arterial hypertension is preferred over primary pulmonary hypertension,71 as are the more specific terms for the conditions previously referred to as secondary. 1100 Arch Pathol Lab Med—Vol 133, July 2009

A limitation of the clinical classification is that it does not incorporate histologic findings seen on biopsy. This is likely because of the lack of concordance between histologic findings and clinical response to therapy.72 Indeed, although Heath and Edwards developed a pulmonary arterial hypertension (PAH) grading system,73 it is applicable only to patients with congenital malformations leading to shunting from left to right side. In other clinical settings, the morphologic features described, such as changes in small arteries (medial hypertrophy, intimal proliferation, concentric intimal fibrosis, necrotizing arteritis) and changes in arterioles (muscularization, plexiform lesions [Figure 7], angiomatoid lesions) are useful in identifying the range of pathologic conditions encountered in IPAH. When tissue is available from all lobes for sampling (eg, explanted lungs and autopsies), the whole range of pathologic changes are often seen in the same patient. Idiopathic pulmonary arterial hypertension remains mostly a clinical diagnosis because patients with this condition do not typically undergo biopsy. In practice, the different types of PAH (World Health Organization group I) have in common small pulmonary muscular arteriole lesions, as well as similar clinical respiratory symptoms and similar response to therapy.71 These similarities imply a unifying disease mechanism, a concept that requires further study. Recent studies into a possible disease mechanism have focused on 3 general areas: autoantibodies, endothelial progenitor cells, and pulmonary arterial smooth muscle cells. Pulmonary arterial hypertension in patients with systemic sclerosis (SSc-PAH), which falls into the APAH category, is a major cause of mortality in this population.74,75 Autoantibodies to fibroblasts have recently been identified in both patients with SSc-PAH and IPAH; the antigenic targets of these autoantibodies include proteins involved in several key cellular pathways, including cytoskeletal function and cellular metabolism.76 Anti–endothelial cell antibodies have also been described for patients with SSc-PAH and IPAH.77 Junhui et al78 showed decreased numbers and activity of endothelial progenitor cells isolated from patients with IPAH, as compared to healthy individuals. These findings suggest that these progenitor cells may be a valid therapeutic target for patients with PAH, and an open-label pilot study in children with PAH has confirmed the safety and efficacy of autologous transplantation of endothelial progenitor cells.79 Another major area of research has been the study of pulmonary arterial smooth muscle cells and the transforming growth factor ␤ (TGF-␤) receptor complex, which is a key regulator of vascular smooth muscle homeostasis.80 Several mutations in the TGF-␤ type II superfamily receptor bone morphogenetic protein receptor 2 are known to occur in both FPAH81,82 and IPAH.83 ASTHMA Asthma and chronic obstructive pulmonary disease are common obstructive lung diseases with a spectrum of symptoms, and both inflammation and airway remodeling are important factors involved in their pathogenesis. While the basic histopathologic changes associated with remodeling (eg, subepithelial fibrosis, increased smooth muscle content, mucus gland hyperplasia) are widely recognized, there are now new insights into the complex interaction between the various airway components, including cytokine and chemokine release, vascular remodeling Update in Nonneoplastic Lung Diseases—Gordon et al

and angiogenesis, and the inflammatory response.84,85 Indeed, studies of noninvasive markers of airway inflammation have recently led to the concept of reclassifying asthma into eosinophilic and noneosinophilic phenotypes,86 which may help explain the observed differences in prognosis and treatment response in patients with obstructive respiratory disease. A small early study by Wenzel et al87 determined that a subset of patients who had severe asthma with nearly normal numbers of eosinophils in endobronchial biopsy specimens could be physiologically and clinically distinguished from patients who had severe asthma with increased eosinophils. More recently, Simpson et al used the less invasive technique of induced sputum to define eosinophilic and noneosinophilic asthma and defined 4 subphenotypes: eosinophilic (increased eosinophils only), neutrophilic (increased neutrophils only), mixed inflammatory (increased eosinophils with increased neutrophils), and paucigranulocytic (normal eosinophils with normal neutrophils).86,88 While noninvasive techniques of assessing the inflammatory process are preferred clinically for a variety of reasons, little is known about the degree to which histopathologic (Figure 8) and pathophysiologic features of airway inflammation and remodeling correspond to noninvasive markers of airway inflammation. More studies are therefore needed to assess the correlations between invasive and noninvasive parameters and clinical outcomes in patients with obstructive pulmonary diseases. Although patients with obstructive symptoms do not often undergo biopsy, some asthma centers are beginning to obtain more of these specimens. When evaluating biopsy specimens from patients with obstructive lung disease, attention should be given to epithelial denudation and metaplasia, basement membrane thickening, smooth muscle hypertrophy, disorganization of elastic fibers, and both intraepithelial and submucosal inflammatory cells, especially eosinophils and neutrophils. A comment regarding the presence or absence of granulomas and vasculitis is also helpful for clinicians. INTERSTITIAL LUNG DISEASE In 2002, the ATS/ERS published a joint statement describing the classification of idiopathic interstitial pneumonia.89 This classification schema uses an agreed-upon set of histopathologic criteria as a foundation for making a diagnosis, ultimately incorporating radiologic findings as well as the dynamic clinical picture. Several important concepts regarding the histopathologic diagnosis of interstitial pneumonias were clarified in their statement and are discussed below. Bronchiolitis Obliterans Organizing Pneumonia Versus Organizing Pneumonia A longstanding controversy has existed over the use of the term bronchiolitis obliterans organizing pneumonia. This term unfortunately incorporates terminology that is histologically inaccurate for the finding of Masson bodies within terminal airways and that is more accurately applied to the submucosal airway fibrosis in the setting of chronic lung transplant rejection (bronchiolitis obliterans syndrome). Also, the term bronchiolitis obliterans organizing pneumonia can be confused clinically with the entity of constrictive bronchiolitis or obliterative bronchiolitis. The preferred terminology adopted by the 2002 ATS/ERS for Arch Pathol Lab Med—Vol 133, July 2009

the histologic finding of fibroblastic nodules filling terminal airways and alveoli is ‘‘organizing pneumonia’’ (Figure 9) and this correlates with the clinical diagnosis of cryptogenic organizing pneumonia.90 Histologically, organizing pneumonia may or may not have a bronchiolar component and there is preservation of lung architecture. The intraluminal plugs are patchy and are composed of fibroblasts and myofibroblasts in a loose connective tissue with an associated mild interstitial infiltrate of lymphocytes, plasma cells, and histiocytes. The finding of granulomas, abscesses, necrosis, or vasculitis should prompt consideration of alternative diagnoses. Lymphoid Interstitial Pneumonia Lymphoid interstitial pneumonia (LIP) is an interstitial lung disease characterized by diffuse and dense infiltration of alveolar septae by chronic inflammatory cells, including T lymphocytes, plasma cells, and histiocytes, with prominent germinal centers and hyperplasia of the bronchial-associated lymphoid tissue. Many of the reported cases of LIP in the literature are now accepted as being low-grade, B-cell, mucosa-associated lymphoid tissue lymphomas (MALT), and idiopathic LIP is exceedingly rare.91 Cases of true LIP are often associated with underlying autoimmune or immune-mediated systemic diseases, including pediatric HIV/AIDS92 (Figure 10) and combined variable immunodeficiency, a primary immunodeficiency characterized by abnormal immunoglobulin production and associated T-cell abnormalities.93–95 Along the same spectrum as LIP, nodular lymphoid hyperplasia (previously termed lymphoid pseudotumor)—although also historically including cases of B-cell MALT lymphomas—is thought to be a distinct entity based on immunohistologic and molecular studies.96 Usual Interstitial Pneumonia The most common histologic subtype of chronic interstitial lung disease is usual interstitial pneumonia (UIP), which makes up 47% to 71% of cases.97 In the absence of an underlying etiology, it is also known as idiopathic pulmonary fibrosis. Usual interstitial pneumonia can occur in a familial pattern or in the setting of connective tissue disease, hypersensitivity pneumonitis, or drug toxicity. Typically, patients present with gradual-onset dyspnea, nonproductive cough, and restrictive pulmonary function tests in their fifth to seventh decade of life.89 The disease is more common in men, and the median length of survival after diagnosis is 3 years.89 Computed tomography scans demonstrate basilar and interstitial reticular opacities with traction bronchiectasis, honeycombing, and ground-glass opacities. Occasionally, UIP undergoes acceleration or acute exacerbation with no apparent inciting factor, with a mortality rate as high as 50%.98 Treatment for UIP is controversial, with corticosteroids and immunosuppressive drugs being the most commonly used agents. The ATS/ERS supports prednisone therapy with azathioprine or cyclophosphamide for at least 6 months.99 A lung transplant is the best option for patients younger than 70 years and is associated with a 5-year survival rate of 50%.99 Surgical lung biopsy remains the gold standard for diagnosis of UIP, and sampling at least 2 sites is recommended.99 Key histologic features, as identified by the ATS/ERS 2002 consensus, include patchy subpleural and paraseptal distribution of remodeled lung architecture Update in Nonneoplastic Lung Diseases—Gordon et al

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Figure 8. Asthma. A, In this biopsy, there is subbasement membrane fibrosis and eosinophils within the epithelium and in the submucosa. B, This biopsy from a different patient shows a predominance of neutrophils, especially within the epithelium (hematoxylin-eosin, original magnifications ⫻400 [A and B]). Figure 9. Organizing pneumonia. An intra-alveolar fibroblastic nodule (Masson body) is seen streaming from alveolus to alveolus. Adjacent foamy macrophages indicate obstruction (hematoxylin-eosin, original magnification ⫻400). Figure 10. Lymphoid interstitial pneumonia. A substantial lymphocytic infiltrate is seen expanding the interstitial space in this lung wedge biopsy from a 5-year-old child who presented with dyspnea as the initial manifestation of human immunodeficiency virus infection (hematoxylin-eosin, original magnification ⫻40). Figure 11. Usual interstitial pneumonia. A, Fibroblastic foci are associated with bronchial metaplasia in this area of microscopic honeycombing. 1102 Arch Pathol Lab Med—Vol 133, July 2009

Update in Nonneoplastic Lung Diseases—Gordon et al

or other interstitial disease processes.89 The differential diagnosis for UIP also includes fibrosing nonspecific interstitial pneumonia (less architectural distortion), desquamative interstitial pneumonia/respiratory bronchiolitis– associated interstitial lung disease (more intra-alveolar macrophages), chronic hypersensitivity pneumonitis with fibrosis (less cellular, with granulomas), organizing pneumonia (intra-alveolar fibrosis) and Langerhans histiocytosis (predominance of peribronchiolar fibrosis and stellate-shaped scars). Despite what is known about the morphologic features of UIP, the pathogenesis of this disease remains elusive. The current hypothesis presumes injury to the alveolar epithelium, followed by inflammatory and fibrotic tissue repair, which fails to abate. The fibroblastic focus appears to play a major role in the progression of this disease and serves as a prognostic marker, with more foci imparting a worse prognosis.100 Many hypotheses exist regarding the origin of these fibroblasts, including resident pulmonary mesenchymal cells, epithelial cells that have undergone mesenchymal transition, and most recently, bone marrow– derived circulating fibrocytes.101,102 Patients with IPF have increased numbers of fibrocytes in peripheral blood103 as well as in scarred areas of lung near fibroblastic foci.102 Furthermore, recent literature suggests that there may be a differential resistance to apoptosis between fibroblasts and epithelial cells, with fibroblastic foci more resistant and epithelial cells more susceptible to apoptosis.104 Undoubtedly, the mechanism of disease is complex and requires further investigation to better understand the pathogenesis of and to improve treatment strategies for UIP.

Figure 12. Usual interstitial pneumonia. Gross appearance of a lung at autopsy shows the predominantly lower-lobe fibrosing process with subpleural honeycombing (inset). Figure 13. Nonspecific interstitial pneumonia. Preserved alveolar architecture with uniform fibrosis and inflammation of the alveolar walls and areas of bronchial metaplasia are characteristic features (hematoxylin-eosin, original magnification ⫻40).

with dense fibrosis, frequent honeycombing, and large fibroblastic foci scattered at the edges of dense scars.89 Temporal and spatial heterogeneity are the hallmarks: temporal variation is represented by young, pale fibroblastic foci adjacent to areas of older, denser pink collagenous fibrosis (Figure 11); spatial variation indicates that these collagenous areas are arranged in islands adjacent to normal parenchyma or areas of honeycombing, which is characterized by groups of dilated air spaces lined by metaplastic bronchiolar epithelium (Figure 12). On the other hand, inconspicuous or absent in UIP are granulomas, eosinophilia, dust deposits, chronic interstitial inflammation,

Nonspecific Interstitial Pneumonia Nonspecific interstitial pneumonia (NSIP) was originally classified as a provisional entity by the 2002 ATS/ERS classification, pending further studies of the associated clinical characteristics.89 Travis et al recently reported their findings from such studies and concluded that idiopathic NSIP is a distinct clinical-radiologic-pathologic entity, occurring primarily in middle-aged women who are never smokers, with a 5-year survival rate greater than 80%.105 Major features of NSIP are its often patchy distribution of uniform interstitial thickening by a cellular or, more often, a fibrosing process (Figure 13). Common features of both subtypes include lymphoid follicles, enlarged air spaces (not microscopic honeycombing), some degree of interstitial inflammation, focal organizing pneumonia, pleural fibrosis, and vascular medial thickening.105 The major differential diagnosis is usual interstitial pneumonia, which has patchy, lower-lobe predominant fibrosis with temporal heterogeneity. Fibroblastic foci are a prominent feature of UIP, whereas their presence in NSIP is usually inconspicuous. Finding poorly formed granulomas and intraluminal fibrosis is more consistent with hypersensitivity pneumonitis than with NSIP, and prominent intraluminal fibroblastic nodules (Masson bodies) with preserved underlying architecture are more likely to be seen in organizing pneumonia. The pathologic pattern of NSIP is seen in more patients than just those with the distinct clinical-radiologic-patho-

← B, Interstitial fibrosis and fibroblastic foci in the subpleural lung with extension along interlobular septum (hematoxylin-eosin, original magnifications ⫻40 [A and B]). Arch Pathol Lab Med—Vol 133, July 2009


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logic picture of the disease. The histologic NSIP pattern is often seen in lung biopsies of patients with collagen vascular disease—even as an initial presentation—as well as in those of patients with occupational exposures.106 There may be some differences in the collagen and elastic fiber deposition, which correlate with prognosis, in NSIP associated with fibrosing and collagen vascular disease as compared with cellular NSIP.107 Therefore, a diagnosis of NSIP from a lung biopsy should prompt efforts to identify an etiology so that proper therapy can be pursued. CONCLUSION Nonneoplastic lung diseases encompass a variety of pathologic entities. Advances in our understanding of several of these entities may affect their diagnosis, management, and treatment. Systematic assessment of microscopic features, in conjunction with clinicoradiologic data, is an important key to a successful diagnosis by the wellinformed surgical pathologist. References 1. deMello DE. Pulmonary pathology. Semin Neonatol. 2004;9(4):311–329. 2. Hamvas A, Cole FS, Nogee LM. Genetic disorders of surfactant proteins. Neonatology. 2007;91(4):311–317. 3. Tokieda K, Ikegami M, Wert SE, Baatz JE, Zou Y, Whitsett JA. Surfactant protein B corrects oxygen-induced pulmonary dysfunction in heterozygous surfactant protein B-deficient mice. Pediatr Res. 1999;46(6):708–714. 4. deMello DE, Nogee LM, Heyman S, et al. Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B deficiency. J Pediatr. 1994;125(1):43–50. 5. Vorbroker DK, Profitt SA, Nogee LM, Whitsett JA. Aberrant processing of surfactant protein C in hereditary SP-B deficiency. Am J Physiol. 1995;268(4): 647L–656L. 6. Ballard PL, Nogee LM, Beers MF, et al. Partial deficiency of surfactant protein B in an infant with chronic lung disease. Pediatrics. 1995;96(6):1046–1052. 7. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004; 350(13):1296–1303. 8. Ban N, Matsumura Y, Sakai H, et al. ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J Biol Chem. 2007;282(13):9628–9634. 9. Nogee LM. Genetics of pediatric interstitial lung disease. Curr Opin Pediatr. 2006;18(3):287–292. 10. Tredano M, Griese M, Brasch F, et al. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A. 2004;126(1):18–26. 11. Dirksen U, Nishinakamura R, Groneck P, et al. Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J Clin Invest. 1997;100(9):2211–2217. 12. Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colonystimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A. 1994;91(12):5592–5596. 13. Dranoff G, Crawford AD, Sadelain M, et al. Involvement of granulocytemacrophage colony-stimulating factor in pulmonary homeostasis. Science. 1994; 264(5159):713–716. 14. Ikegami M, Ueda T, Hull W, et al. Surfactant metabolism in transgenic mice after granulocyte macrophage-colony stimulating factor ablation. Am J Physiol. 1996;270(4):650L–658L. 15. Yoshida M, Ikegami M, Reed JA, Chroneos ZC, Whitsett JA. GM-CSF regulates protein and lipid catabolism by alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2001;280(3):379L–386L. 16. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003;349(26):2527–2539. 17. McKercher SR, Torbett BE, Anderson KL, et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 1996;15(20): 5647–5658. 18. Anderson KL, Smith KA, Conners K, McKercher SR, Maki RA, Torbett BE. Myeloid development is selectively disrupted in PU.1 null mice. Blood. 1998; 91(10):3702–3710. 19. Shibata Y, Berclaz PY, Chroneos ZC, Yoshida M, Whitsett JA, Trapnell BC. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001;15(4):557–567. 20. Nakata K, Kanazawa H, Watanabe M. Why does the autoantibody against granulocyte-macrophage colony-stimulating factor cause lesions only in the lung? Respirology. 2006;(suppl 11):65S–69S. 21. Thomassen MJ, Barna BP, Malur AG, et al. ABCG1 is deficient in alveolar macrophages of GM-CSF knock-out mice and patients with pulmonary alveolar proteinosis. J Lipid Res. 2007;48(12):2762–2768. 22. Bonfield TL, Farver CF, Barna BP, et al. Peroxisome proliferator-activated

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