The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD.
Key points
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Although there is substantial histologic overlap among the pulmonary manifestations of different connective tissue diseases (CTDs), certain patterns may favor 1 CTD over another; occasionally, distinctive histologic clues may be present.
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CTDs may present with acute, subacute, and/or chronic pleuropulmonary manifestations, often mixed within the same biopsy, representing ongoing disease.
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Patients with CTD may be taking immunosuppressive medications and are vulnerable to certain infections; both of these can result in histologic changes that are similar to direct pulmonary manifestations of the underlying CTD and can represent diagnostic dilemmas for the pathologist.
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A multidisciplinary approach involving the pathologist, rheumatologist, pulmonologist, and radiologist allows for correlation of the clinical, radiologic, and pathologic findings to arrive at the proper diagnosis.
Introduction
The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns that can vary greatly within a given CTD and may in fact display significant overlap between distinct CTDs. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung, including the airways, alveolar septa, alveolar spaces, pleura, and vasculature, and often demonstrate acute, subacute, and chronic lesions within the same specimen, indicating an ongoing pathophysiologic process. All CTDs can result in nonspecific histologic patterns that are essentially indistinguishable from the idiopathic interstitial pneumonias; however, in the setting of known CTD, the probability that the lung findings are caused by the patient’s underlying systemic disease must be considered. Certain histologic patterns do tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy.
Some pulmonary pathologies seen in patients with CTD may not be a direct manifestation of the effect of CTD on the lung, but may be related to therapy or to other systemic complications of the patient’s CTD. These conditions can result in significant histologic changes that can make it difficult to determine which findings can be truly be ascribed to involvement by the patient’s CTD. For example, a patient with rheumatoid arthritis (RA) treated with methotrexate may develop a cellular nonspecific interstitial pneumonitis (NSIP) secondary to drug toxicity; this may mimic cellular NSIP that could represent the bona fide onset of RA-associated ILD, or it could mimic the histologic pattern of a viral pneumonia to which the patient would be predisposed secondary to immunosuppression. The recognition and contextualization of these processes are best accomplished via review by a multidisciplinary team, including pathologists with specialized training in thoracic pathology or significant experience reading non-neoplastic surgical lung biopsies, rheumatologists, pulmonologists, and radiologists. This article will cover the pulmonary pathologies seen in RA, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD.
Introduction
The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns that can vary greatly within a given CTD and may in fact display significant overlap between distinct CTDs. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung, including the airways, alveolar septa, alveolar spaces, pleura, and vasculature, and often demonstrate acute, subacute, and chronic lesions within the same specimen, indicating an ongoing pathophysiologic process. All CTDs can result in nonspecific histologic patterns that are essentially indistinguishable from the idiopathic interstitial pneumonias; however, in the setting of known CTD, the probability that the lung findings are caused by the patient’s underlying systemic disease must be considered. Certain histologic patterns do tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy.
Some pulmonary pathologies seen in patients with CTD may not be a direct manifestation of the effect of CTD on the lung, but may be related to therapy or to other systemic complications of the patient’s CTD. These conditions can result in significant histologic changes that can make it difficult to determine which findings can be truly be ascribed to involvement by the patient’s CTD. For example, a patient with rheumatoid arthritis (RA) treated with methotrexate may develop a cellular nonspecific interstitial pneumonitis (NSIP) secondary to drug toxicity; this may mimic cellular NSIP that could represent the bona fide onset of RA-associated ILD, or it could mimic the histologic pattern of a viral pneumonia to which the patient would be predisposed secondary to immunosuppression. The recognition and contextualization of these processes are best accomplished via review by a multidisciplinary team, including pathologists with specialized training in thoracic pathology or significant experience reading non-neoplastic surgical lung biopsies, rheumatologists, pulmonologists, and radiologists. This article will cover the pulmonary pathologies seen in RA, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD.
Histology of lung disease in rheumatoid arthritis
Perhaps more so than any of the other CTDs, lung disease in patients with RA exhibits a wide variety of histopathologic patterns that can affect all of the major compartments of the lung. Pleural effusion and pleuritis are common initial pleuropulmonary manifestations of RA and may be appreciated grossly and microscopically as acute fibrinous pleuritis, fibrous pleural thickening, and/or pleural adhesions. Cytologic preparations of pleural fluid may have characteristic aggregates of amorphous debris and degenerated neutrophils. Single or multiple rheumatoid nodules ( Fig. 1 ) may be found in the pleura, interlobular septa, or alveolar interstitium; although not the most common manifestation, they are considered the most specific finding of RA-ILD. These nodules, which can measure up to 2 to 3 cm, are identical to those seen in the subcutaneous tissues, consisting of sterile central necrobiosis surrounded by epithelioid histiocytes.
The most frequent histologic patterns of ILD among RA patients are NSIP ( Fig. 2 ), followed closely by usual interstitial pneumonia (UIP) ( Figs. 3 and 4 ), accounting for 30% to 67% and 13% to 57% of RA-associated ILD, respectively. Some studies have noted an equal or greater incidence of UIP histology in RA-ILD, although smaller sample sizes and the high frequency of both ILD patterns among this patient population may account for the discrepancy. The histologic appearance of RA-associated NSIP (RA-NSIP) or UIP (RA-UIP) is identical to that seen in idiopathic NSIP and UIP, although the occurrence of more prominent interstitial lymphoid aggregates, either within alveolar septal walls or associated with small airways, has been noted in several studies. Indeed, the presence of lymphoid aggregates, and specifically germinal centers, has been reported to be significantly greater in RA-UIP than in UIP, and has been suggested to be a distinguishing feature of RA-ILD. Similarly, the frequency of fibroblast foci has been reported to be lesser in RA-UIP than in idiopathic UIP.
Various types of inflammatory airway disease including bronchiectasis, chronic bronchitis, and follicular bronchiolitis are often seen as a secondary finding in a background of NSIP or UIP. Acute and subacute processes such as diffuse alveolar damage (DAD) and organizing pneumonia (OP) can be seen in patients with established RA-ILD, often in the clinical setting of an acute exacerbation, but they can occasionally represent the initial pulmonary manifestation of RA. Vasculitis, capillaritis, and pulmonary hemorrhage are rare acute manifestations of RA-ILD; chronic vascular manifestations, when present, are usually a result of underlying fibrotic lung disease.
Histology of lung disease in systemic sclerosis (scleroderma)
ILD occurs in up to 80% of patients with systemic sclerosis (SSc), making ILD more prevalent in SSc than in any other CTD. The most characteristic histologic features of ILD in SSc are dense interstitial fibrosis and pulmonary hypertensive vascular changes. The most common pattern of interstitial fibrosis in SSc is fibrotic NSIP ( Fig. 5 ), manifesting as dense, paucicellular interstitial fibrosis that maintains the underlying lung architecture and often spares the immediate subpleural area. As the lung disease progresses, the areas of fibrosis may become confluent and appear as honeycomb or end-stage lung. Patients with SSc may also manifest their ILD as a typical UIP pattern with temporal and spatial heterogeneity, in contrast to the diffusely uniform fibrosis of NSIP. The pulmonary hypertensive vascular changes ( Fig. 6 ) are manifested as concentric intimal thickening by fibromyxoid tissue and mild medial hypertrophy leading to thickened and stenotic pulmonary arterioles. The degree of pulmonary hypertensive changes is often more severe and out of proportion to the degree of interstitial fibrosis. Although true vasculitis and pulmonary hemorrhage can occasionally be seen, it is a fairly uncommon feature in this disease. Patients with SSc often have esophageal dysmotility with associated gastrointestinal reflux; this can lead to superimposed aspiration pneumonia that may or may not be clinically apparent but can complicate the interpretation of the surgical lung biopsy.
Histology of lung disease in myositis
Chronic pulmonary disease in polymyositis and dermatomyositis (PM-DM) consists of varying degrees of cellular interstitial pneumonitis that are best characterized as NSIP ( Fig. 7 ). Most case series have described varying degrees of fibrosis accompanying the cellular interstitial infiltrates of PM-DM, including 1 study indicating approximately a 40% prevalence of cellular NSIP and 53% prevalence of mixed cellular and fibrotic NSIP in myositis patients, with only rare cases of pure fibrotic NSIP. The OP pattern ( Fig. 8 ) can be seen in PM-DM patients, either as an isolated manifestation or superimposed on a background of NSIP, and it has been histologically confirmed to resolve with steroid treatment. UIP pattern histology has been described in PM-DM and, similar to RA-UIP, it often contains at least moderately cellular areas consisting of lymphoplasmacytic or mononuclear infiltrates. The UIP pattern may arise more frequently in patients with the antisynthetase antibody Jo-1. DAD is occasionally seen as a more acute manifestation of PM-DM lung disease in the clinical setting of acute exacerbation of underlying chronic lung disease, and it typically carries a poor prognosis similar to DAD associated with the clinical entity of acute respiratory distress syndrome. Other more florid cellular manifestations of ILD, such as follicular bronchiolitis and lymphoid interstitial pneumonia (LIP) are rare in PM-DM. Other rare manifestations of ILD associated with PM-DM include diffuse alveolar hemorrhage (DAH), pleuritis, airway involvement, and vasculitis.
Histology of lung disease in systemic lupus erythematosus
Pleuritis is the most frequent pleuropulmonary manifestation of systemic lupus erythematosus (SLE), and it appears histologically as nonspecific inflammation, fibrin deposition, and pleural fibrosis ( Fig. 9 ). Cytologic preparations of pleural fluid from SLE patients may show pathognomonic lupus erythematosis cells consisting of neutrophils or macrophages with intracytoplasmic remnants of degenerated nuclei.
